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

Ladies and gentlemen, thank you for standing by. Greetings, and welcome to the TG Therapeutics webinar. [Operator Instructions] As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Jenna Bosco. Please go ahead.

Good morning, everyone, and thank you all for joining us. My name is Jenna Bosco, and I'm Head of Corporate communication for TG Therapeutics. And we're very excited to share with you all today a preview of the ULTIMATE I and II Phase III trial results. Before we begin, I just want to remind everyone that we anticipate making some forward-looking statements based on our current expectations. These statements involve risks and uncertainties that can cause our actual results to differ materially. For a description of these risks and uncertainties, we encourage you to review the disclosures on this slide and also in our latest reports filed with the Securities and Exchange Commission and available on our corporate website at www.tgtherapeutics.com. With that, let's kick off with a quick overview of today's agenda. In a few moments, I will briefly introduce our external speakers who have joined us this morning to discuss the data. And then I'll turn the call over to our CEO, Mike Weiss, to provide some opening remarks. Dr. Steinman will then review the Phase III data highlights, following which we will welcome our external participants to formally introduce themselves and participate in a short panel discussion before opening it up for Q&A. So first, I would like to welcome and introduce Dr. Lawrence Steinman, a Zimmerman Professor of Neurology and Neurological Sciences and Pediatrics at Stanford University and also the global study chair for the ULTIMATE I and II Phase III trials. Dr. Steinman has worked closely with us since we launched our MS program and is a member of the TG Steering Committee. Thank you, Dr. Steinman, for joining us. Next, I'll welcome Dr. Ed Fox, the Director of Multiple Sclerosis Clinic Clinical Texas, in Round Rock, and the clinical Assistant Professor of Neurology at the University of Texas Medical Branch. Dr. Fox served as the study chair of the ublituximab Phase II trial and is also an investigator on our Phase III ULTIMATE trial as well as a member of the TG Steering Committee. Thank you, Dr. Fox, for joining us. And last, but certainly not least, I welcome Dr. Enrique Alvarez, the Assistant Professor of Neuroimmunology and the Medical Director of Outpatient Neurology Department at the University of Colorado, Rocky Mountain Multiple Sclerosis Clinic. Dr. Alvarez served as an investigator on the ULTIMATE trial and has been an adviser and a member of the TG Steering Committee. Thank you, Dr. Alvarez. So with that, let me turn the call over to our CEO, Mike Weiss, for some opening remarks.

Good morning, everybody. Thanks for joining us. I'm going to be super brief. We're very, very excited, obviously, to be presenting this data today. It's been a long time coming, and we're just excited to be able to get the data out for everyone to see. And Dr. Steinman's going to share that with us, and then we're going to have a great panel discussion. So with that, again, super excited, I want everyone to see this presentation. It's very exciting. So Dr. Steinman, I'll turn it over to you.

Thank you, Mike. And why don't we put up the first slide, please? So this morning, I'm going to talk about the results of 2 Phase III trials, ULTIMATE I and ULTIMATE II. I want to thank the study participants, along with my colleagues, and of course, the staff at TG Therapeutics. So ublituximab is an anti-CD20 monoclonal antibody. It targets a unique portion of a molecule called CD20, and it had demonstrated activity in both MS as I'll show you and in tumors. It's glycoengineered. It means it has enhanced potency. One of the advantages of this monoclonal antibody is its short infusion time, 1 hour following the first infusion. Overall, 2,100 patients have been treated with ublituximab, including 3 randomized Phase III trials across multiple sclerosis and hematology. Next slide, please. So the ULTIMATE I and II study designs involve 2 identical Phase III, randomized, multicenter, double-blinded, active controlled studies that were conducted in parallel. And the comparator drug was a drug approved for multiple sclerosis teriflunomide and the experimental drug that we're talking about here is ublituximab, it's given 150 milligrams intravenously on day 1, followed by 450 milligrams IV on day 15 and then every 24 weeks thereafter at week 24, 48 and 72. The placebo also received an infusion until the last day at week 95. So their infusions after the first 1 are given in 1 hour following the first infusion, and we feel this is a very important feature of this therapeutic. Next slide, please. So the objective was to evaluate the efficacy and safety of Ubli, I'll refer to it as Ubli compared with teriflunomide in patients with relapsing multiple sclerosis. The primary endpoint was the annualized relapse rate at 96 weeks. That is the number of confirmed relapses in a year. The key secondary endpoints included imaging variables, including the gadolinium enhancing T1 lesions, the total number of newer enlarging T2 lesions, and then the proportion of subjects with no evidence of disease. The key secondary endpoints were the confirmed disability progression and the subsequent analyses of confirmed disability improvement. And I'll share all of those with you. Next slide, please. So the patient distribution in these 2 studies. The first study had 673 patients. The second study, 660. It was well balanced. The patients that were randomized. You can see 275 versus 274 and the first trial, 273 and 272 in the second trial. Approximately 90% of patients in both arms of both trials completed the study. Ubli, they had 93% completers in ULTIMATE II, 88% completers in ULTIMATE I, but you can see that they were very well matched and tolerated. Next slide. The demographics of the study, we're pretty standard for anti-CD20 studies, the age 37 versus 36. There was a preponderance of females as there is for multiple sclerosis. And you can see through the various columns that there was good randomization between the Ubli group and the teriflunomide group. So that was satisfactory and, of course, very important. Let's go on to the next slide. So to get to the part of the matter, the primary endpoint, in my opinion, was really quite impressive. There was a 60% reduction compared to teriflunomide in the first study, 49% in the second study, the p-value is showing the significance, have a lot of zeros in them. It was very impressive. But most impressively, we in the field have thought that there's a barrier at about 0.1. No trial had succeeded in getting the annualized relapse rate before this -- below this barrier. And as you can see in the ULTIMATE I trial, the rate was 0.07 in the second trial, 0.09, 0.1 means that there is 1/10 of a relapse per year. So this is getting very impressive. And really for a primary endpoint, I don't want to use [indiscernible] of adjectives, but you can tell from my voice, these are great results. Next slide, please. The total number of gadolinium lesions also revealed really impressive reductions, 97% in ULTIMATE I, 96% and ULTIMATE II statistically, these were highly significant. Next slide, please. The number of new or enlarging T2 lesions, again showed 92% reduction in ULTIMATE I, 90% reduction in ULTIMATE II. Next slide. So the confirmed disability progression, both the teriflunomide and the Ubli did well, but 95% of the patients on Ubli had no disability progression. These results were not statistically significant because generally, very few patients had any progression at all. Next slide. However, quite impressively and something that I enjoy telling patients when they go into the room that there was significant improvement and this confirmed disability improvement is yet another feature of this drug that you can look a patient in the eye and tell them that there was a significant level of improvement compared to the teriflunomide in this experiment. So there was a 100% increase. So for teriflunomide in Ubli, 188% in the ULTIMATE II. And both of those results are highly significant. So clinical improvement is a feature seen in these trials. Next slide. And also of great importance is this measure called no evidence of disease activity. There's no relapses. There's no progression and there's no MRI activity. And in these trials in the ULTIMATE I, there was 198% improvement compared to teriflunomide and ULTIMATE II, 277% improvement. So these are really striking results, highly statistically significant. So when looking at the overall relapse rate, looking at the disability progression improvement, looking at imaging and here, looking at no evidence of disease activity. Ubli is quite impressive. Can we go to the next slide, please? So adverse events are laid out here, there were more infusion reactions in the ublituximab compared to teriflunomide. But the next slide will show that these infusion reactions, if we can go to the next slide, were rarely considered serious. The other adverse events included infections and other nervous system disorders, but they were pretty evenly matched in the 2 groups. The next slide. The infusion-related reactions were generally mild to moderate. The Grade 4 reactions were very small. And also, with repeated infusions, there was a decrease in the frequency of these reactions over time. So the preponderance of the reactions we're seeing on the first infusion. The next slide. So just to summarize here, in the Phase III, the 2 ULTIMATE I and II studies. There was a significantly reduced annualized relapse rate, significantly reduced MRI parameters compared with teriflunomide. There was a very low rate of disability progression observed with Ubli with 94% of patients showing no 12-week disability progression in the ULTIMATE I and 96% showing no 24-week progression in ULTIMATE II. Neither were statistically significant. However, Ubli increased the proportion of patients with 12-week confirmed disability improvement and 24-week disability improvement. A significantly higher percentage of patients treated with Ubli compared with teriflunomide achieved no evidence of disease. And there was a quite a favorable safety and tolerability profile with really no unexpected safety signals. So in the 2 Phase III trials, ULTIMATE I and II, Ubli, with the benefit of a 1-hour infusion, demonstrated robust activity and a favorable safety profile that serves as a benefit for individuals with relapsing multiple sclerosis. Next slide.

Great. Thank you, Dr. Steinman. That was excellent. I really appreciate that and the time you've taken to work with us and review and analyze the data with us. So thank you for that. So I think at this time, we're going to let each of the expert panelists. Just give a little background on themselves, their practice, just to get a sense of where they are coming from both geographically and medically and scientifically. We know where Dr. Alvarez is coming to us from, for sure. So that one's pretty easy. But yes, if we could start with going in the order on the slide, maybe Dr. Steinman, if you can -- Jenna gave great introductions to everybody already. I was just a little more about your practice areas and things that you're interested in.

So I've been a professor at Stanford for 40 years. I see adults and children with multiple sclerosis, and I run a busy research lab in the area of multiple sclerosis. I was delighted to serve as global investigator with this trial. And again, I'd really like to thank the individuals who participated in the trial. We owe a lot to them.

Dr. Fox?

Yes. Edward Fox, I'm -- I've been in Central Texas and Austin since 1992 in clinical practice. I'm in a private practice. There are 5 providers in it and I'm the MS specialist in that group. We have our own building. We have our on-site infusion suite. So we actually provide the care for the MS patients in our own infusion suite, and they're not affiliated with a hospital. We have been involved in Phase III clinical trials since the mid-2000s, been involved in clinical trials on pretty much all the products that are on the market right now. And was the lead for the Phase II trial for ublituximab as well.

Thank you.

I'm Enrique Alvarez. I'm one of the assistant professors and part of the MS group at the University of Colorado in the metro area in a suburb called Aurora. I've been here for about 8 years now, been involved with peripherally with the Phase II study and was the site investigator for the Phase III trial. And kind of really believe in sort of high efficacy treatment early with -- for the treatment of MS patients. And so excited to kind of have the data come out just because it looks so promising, as Dr. Steinman presented.

Excellent. Thank you. Okay. So I think we're going to do a quick -- before we go to the open Q&A, we thought we'd ask the panelist some general questions that we get quite a bit, not very specific into TG and ublituximab, but more just general landscape sort of question. So the first one that we thought was how has the MS treatment last get evolved over the last 5 years. So I'll open it up, whatever wants to jump in, feel free to jump in and give some thoughts.

Ed, why don't you kick off?

Yes. In the last 5 years, there's certainly been a change in the mindset for the newly diagnosed MS patient with relapsing MS. We used to talk about platform medications and escalation therapy. And there's just not a lot of discussion about that anymore. The initial therapies that we were using 15 years ago are used in much smaller percentages really only for specialized cases. Now we're looking at more high efficacy medications from the beginning because we're looking for the outcomes like you see today, which is a much higher incidence of being able to achieve no evidence of disease activity. That's what the patients want, that's what the providers want. And so I think the landscape by adding an entire category of medicines, the CD20 depleters and being able to have choices within the categories of the high efficacy medications has changed the initial conversation and also lowered the bar for what people have to see to want to change medicine from their existing medicines. They're no longer satisfied with partial responsiveness to whatever medication they're on is a disease modifying therapy.

Excellent. Dr. Alvarez, Dr. Steinman, anything to add as we move again, I think we're going to move pretty quickly into the next topic anyway.

Yes. I'd just like to say that [indiscernible] what Dr. Fox said that for this disease, it's very serious, and the idea is to come in strong and early and arrest the disease as best we can with the reagents, the drugs that really have the most efficacy. We'll talk about convenience and the other questions, but we're no longer happy to give the older drugs and wait for things not to go well before advancing to the more powerful drugs. The idea now is let's do it early and stop the disease.

And to that point, do you think that, that is now generally a recognized approach across all of MS treating physicians in the U.S., let's say, for the moment, you think that's generally recognized? Or you think that's still maybe isolated to certain centers, and it hasn't really gotten out to the -- see everyone?

It seems to be a very general trend. And I'd really like the further perspective of my 2 colleagues, but that's my opinion, that the trend is to go strong and early.

Yes. I would say in the last probably 2 to 3 years already with kind of the introduction of ocrelizumab as more and more people are feeling comfortable with it. That we're starting to see a lot more push to kind of getting into the higher efficacy therapies earlier. And so I think compared to 10 years ago when I started my fellowship and orals came out about a few months after starting my fellowship. These medications have really just become available, right? And so it's not like we have a huge amount of experience with these highly efficacious treatments and usually, there's a little bit of an inertia to kind of change therapies. So it's taking a little bit of time. And I think what we see now is probably a representation of things that happened 2 to 3 years ago as far as number of patients on certain groups of therapies. But I think it's something like 1/3 of patients are already on orals and about 1/3 of patients are already on B-cell therapies. These are kind of the latest numbers that I've been sort of hearing, at least for kind of -- especially for newer starts. And so just a tremendous amount of change and kind of much more of a push towards those higher efficacy therapies.

I would just add that there's better access to IV treatments now than there was even 5 years ago. So I've mentioned that I'll have infusion suite operating in our practice in our building. But if it didn't exist, there would still be outpatient treatment centers where medications can be given IV on a regular basis and it doesn't have to be an oncology center. Just general infusions. And because there are multiple in the area now, I think general neurologists, non-MS specialists, feel like it's not a burden to be able to refer patients for IV therapy, whereas it may have been more difficult especially if they were having to work with a hospital outpatient infusion center.

Great. Thank you. Okay. So we're moving to early with more powerful treatments. And so that certainly, I want to move into CD20 is, of course, since it's an area that we have a lot of interest in here. So where do you view the CD20's fitting in, in the landscape? I guess you can also answer this question in a way of when patient walks in the door, newly diagnosed or someone who comes in needing a new treatment, what percentage of those today, are you putting on to CD20s? This is a pack question because you know Dr. Alvarez is a very big fan of CD20. So I'll let you start, Dr. Alvarez, and then we'll go around the horn here.

Yes, for sure. I mean, I think probably in our center, greater than 80%, probably closer to 90% of patients are probably starting treatment with B-cell therapies. We -- in the state of Colorado, we've had access to rituximab for 10-plus years. And so I think we got a little bit of a head start being able to get access to B-cell therapies in the treatment of MS. And with the approval of OCREVUS in 2017 and that improved access, as Dr. Fox mentioned, the barriers that we were having have kind of come down a lot. And I think we've learned a lot about how to use these medications and kind of more around the safety. I think the concern about infusions as though they must be riskier. But I think the presentation that Dr. Steinman had showing really good safety track record of these medications and our experience long-term matches that up really well, has really kind of pushed the comfort level with using CD20s in the vast majority of patients.

Dr. Fox, where are you these days? And where do you -- otherwise fitting in?

I did not get the head start that Dr. Alvarez did, principally because insurers in Texas, really were not allowing off-label use of rituximab. But as soon as ocrelizumab came on the market, and we've been involved in the Phase III trials. There is a very rapid uptake of people getting on that medicine. So it's about 50% now, I think, for my practice, for new starts being on that therapy. And it's a -- I think it's true now for patients who are being newly diagnosed or trying to consider a switch of medications. That it's very easy for them to find other people that are on this therapy. And so when you already have up to a 30% market share, it no longer seems like you're going with a new and somewhat unproven treatment approach. Now it's much more of the standard. So what's happened now is that it's very easy to put people in touch with each other who are on this therapy to be able to counsel them about whether it's been the right choice for them and to answer their questions.

Yes. I'd go along with that as well. The social media, our individuals that we take care of with MS are really tightly connected. So there's a lot of cross-talk and I think the experience has been so positive that many of the patients at least at Stanford are coming, inquiring whether they can get on it rather than us having to introduce the idea to them. So it's really catching on very well, and I expect it to increase over time.

Excellent. Okay, thanks. So we're going to do the last question before we go to the open Q&A. This one, again, getting even a little closer to home. So I guess the question is, we know that the subcu CD20 has recently entered the market. So I don't know how much experience you have with patient preference thus far. And I would throw in physician preference, too. So let's not rule out the physician preference here. So to date, the experience with patient preference and physician preference for the subcu CD20 versus the IV form in the market today. Any color or guidance you can give on that?

I'll jump in on this one, again, involved in the Phase III trials to have some people to say that I've had it for a long time, and I was involved in the auto-injector trial as well to see somewhat patient preference and tolerability, but mostly just the ease of use of the auto-injector for subcu. Ofatumumab has been well tolerated and well received, certainly. And I think that the choice between the different products is going to be very similar to the kind of process that went into interferons many years ago with preference that it may not be the same from one provider to another. It will be nice to have the choices. But -- and being able to have every 6-month treatment versus every month treatment, how much the person with MS to think about? When it's time for treatment? What degree of independence they have from the administration of it. It's going to be somewhat different from person to person, different from rural to urban or suburban locals for the patients themselves. The infusion time, I think, is extremely important because utilization of chairs in infusion suites needs to be maximized. Certainly, if there's one thing the last year with COVID and social distancing is proven, is that much like dentist chairs or hair tresses, you've got to manage time in the chair very efficiently. And so the short or the time for infusion, the better the organization ability can be to get the maximum number of people seeing in a socially distanced area.

I would just like to add from my impression of what patients appreciate, the infusion center is a positive experience. You get to talk to individuals who are experienced with it, and there's a general social bonding. But on the other hand, you don't want to miss a whole half day of school or a full day of work going and coming and sitting and waiting. So I think the 1-hour infusion will have a great advantage. As far as the subcu, it's going to be a comparison with a monthly and it will be devoid of that, I think, truly positive experience at the infusion center. This is just my perspective on it, but I think that market research will probably validate what I'm saying.

I think there's a concept that a lot patients bring up and that's I want to forget that happens. And so the fewer contacts that you have is much appreciated by a lot of patients. And I thought the subcu was probably going to have and sort of like an overwhelming reason by patients. But just yesterday, I was talking with 1 of our patients about this. And the nice thing about this, it's less about the delivery, and it's more about that, okay, I don't have to do the IV except for every 6 months, so twice a year and I'm done. And I see you twice a year, and I imagine around it. And for 6 months, I really just forget that happens. And so it's the other aspect that kind of go with it that people, I think, will continue to kind of look at the IV as options. And then part of forgetting about it is having to spend a little time dealing with it. And so the shorter infusion times is definitely going to be appreciated.

Excellent. Well, thanks for indulging us on a few of our own questions, and now we're going to open it up to the panel. I think Jenna is going to moderate our Q&A session. I've got a number of questions I've seen already have popped on to the screen there. But I'll let you Jenna take it from here.

Sure. Thanks, Mike. Operator, do we want to just remind folks how to ask a question in this high-tech Zoom platform?

[Operator Instructions] Our first question today is coming from Eric Joseph.

Okay. Good. Hopefully, you can hear me.

Yes.

Yes.

Excellent. Great. Okay. So just first, a question on the data and then the question for the Docs on intrinsic practice, and thanks again for hosting this session. I guess, looking at the safety data, you see a slightly higher rate of serious inflection at 4% compared to what's reported with the pivotal studies with ocrelizumab and obinutuzumab. I guess any differences in how serious infection is defined in ULTIMATE compared to those prior pivotals? And for the panel, does that difference in infection risk strike them as meaningful in any way? That's the first question. And then secondly, for the panel, can you just talk about how you're preconditioning patients with ocrelizumab today? Any modifications that you're applying in terms of the use of IV methylprednisone and how much of a convenience advantage does the potential to adopt an oral steroid regimen? How much advantage does that represent in managing patients?

Okay. So let's just -- so I'm highly confident that the definition of SAE would be conserved across all trials. So I don't think there's any difference there. I think I'll make a general comment about the rates of infection. Again, these are going to be immune compromised patients across multiple countries and across the world and each study is going to have a slightly different, I would assume, have slightly different effects. But these are B-cell depleting agents all across the board and infection is always going to be a potential risk. But anyone else on the panel want to say -- has any insight about the infection risks with CD20s generally or specifically about the data of any concern?

I would just make a comment that I think sometimes infections are one of the things that we had wait to make judgment on like real-world practice and kind of start seeing what they look like in our hands. Just sometimes reporting standards, how willing are patients able to report them to us and some of these things become less definitions than sort of what the -- what gets reported out. So I mean, if we hear about it, we report it, but sometimes patients are like, we'll report an infection relative will get the flu and they get the flu and they don't think about it much as associated with the drug or anything else like this, it may not even tell us about it. So that's been at least a little bit of our experience with that. And for the most part, I would tend to think about these in our own experience to the trial was that this was very similar to what we would expect between all these options within the treatment class.

One thing I'd like to add is that during the COVID pandemic, individuals on anti-CD20 have done reasonably well. And I think that, that's an important stress test. And if you can get through the pandemic on your therapeutic, that's a good vote of confidence. I hope we don't have further stress tests like that along the way, but this happened and stood up very well. And I think that's really important to keep in mind.

Maybe a comment also about kind of the drug class in general. I think early when the B-cell therapies came out, we saw a lot of use in patients that probably did not need to be on these drugs and would not benefit from these drugs. Meaning patients that were really disabled, very elderly, who are very prone to infections. And so the -- I think that you would hear a lot of experiences of patients with very serious infections and sepsis and things like this. And you would ask the providers, what these patients look like and there might be bed bound and things like this. Those are not necessarily appropriate patients. I think that's been the emphasis about treating these patients early. When the disability is low, that's where we really see very few complications from these medications and then knowing when to kind of pull the trigger on stopping them or other things like that becomes really important.

Yes. And that's -- those are all great points. One thing I will also add, Eric. Obviously, the study was run during COVID. We have a number of COVID actions through the study, certainly in Europe. So I think time, place and just different studies, it probably accounts for most of any differences, one might see. The second question you asked, Eric was about basically oral premeds versus IV premeds? Was that the question?

Correct. Yes.

Yes. So...

I mean, I think while we're seeing a lot of switching or changes from kind of the original protocols, especially with the premedication regimen was the changing out of Benadryl and especially changing that from IV to PO just because of the sedation and just knocking patients out for the infusions. I think that becomes especially important for the -- as the infusion times get a little bit shorter. If they were long, patients would just kind of sleep it off. But as they get shorter, people are not tolerating that as well and want to kind of get out of there and feel well. We do have a fair number of patients who are not getting premedicated with anything at this point. And so little by little, I think we start to kind of de escalate a little bit premedication regimen, and that's fairly standard.

So by each individual patient as they get further out into their infusions, you would deescalate the premeds?

Yes. Patients just don't want to wait. The time kind of goes into all this, right? So for Methylpred, for example, you get the Methylpred and then you got to wait an hour. So if you cut it out, that saves you an hour from the infusion as well. And so patients just don't want to wait around for that stuff as much. And so patients will come and say, hey, do I really need those premeds and it's led to us to have more and more experience of being able to kind of cut back on those.

Mostly for later and just be clear, mostly for later infusions.

Correct. Yes. Especially for the first infusion, you'd want to premedicate everybody with kind of the standard regimen because as you saw from the number of infusion reactions, there -- it's a decent number with the first one. As you start to peel off, the level of B cells and things like this, the number of infusion reactions really drops off.

Yes. I appreciate in the clinical trial having leeway in this. It was not so dictated about however premedication could go. So we even substituted non-sedating antihistamine medication for the diphenhydramine being able to give oral steroids at home before even coming in was beneficial, although agreed, we did not do that for the initial infusions. We definitely did for subsequent ones and a lot of patients and had excellent results in terms of tolerability.

Our next question today is coming from Alethia Young.

Can you guys hear me?

Yes.

Well, congrats on this is really interesting data. I guess, a couple for me. I just wanted to talk a little bit maybe with the positions about the confirmed disability improvement. I mean, that seems to be very distinctive. So I guess, have you seen it with other MS drugs? What does that mean? Talk a little bit more about what it means to patients, right? Like, I mean, obviously, disability is a big piece of the story line? And then, I guess, the next question also again for physicians is just like less say you had to switch some buy from OCREVUS, I mean, to like, but is it really just a price consideration ultimately? Or do these data give you tools to provide evidence that maybe it might actually be in one's interest to switch?

Thanks, Alethia. Anyones want to jump in. We've got a question about the CDI and it's meaning in terms of this trial, as I say, particularly outstanding result compared to other studies that you've seen in other drugs. I guess we'll start with that question.

I'll start with that we've had other drugs where you are more likely to get better than worse over a 2- year Phase III trial program, and that's kind of an easy message to pass on to patients that there are 3 things that can happen, people get better, stay the same or worsen. And by far, the lowest category was worsen. And so to be able to say you're more likely to get better than worse, is very meaningful for people when they're starting a therapy. They would love to have excellent healing from their initial relapses. So to have really robust data in that regard just strengthens the conversation that we can have with the patients. It's not a promise. It's just basically, here's what we've seen in this, that people who have some degree of disability going into it in early active MS can actually see improvement over time. Healing can happen. And so that's in keeping with clinical trials that we're always talking about wellness and what they can do to help themselves with diet and exercise and stress management and everything else. But it's, I think, part of the bigger picture that patients really can be encouraged by when they hear it. So although it is not unique, the robustness of the data, and I think is going to be a topic of conversation between the prescribers and the patients. And that's what you want to see. Before going on to the second one, I'll let everybody else chime in about that.

I'd agree with that. And I think that the disability improvement and the no evidence of disease combined make for a very comfortable and positive conversation with the individual who you're trying to convince that this is the right drug for their particular disease. So I think the 2 together really enhance each other. Again, the comparison, OCREVUS also shows improvement and similar evidence of no disease appearance. So I think that it then rests on other factors such as the speed of the infusion. But I think in the whole class, this is a very positive message that one can give for these 2 anti-CD20 s by infusion.

Okay. So unless doctor do you want to add anything on top of that point, maybe you could lead us off with the what would drive one to switch from OCREVUS to Ubli? Is it the one our fusion? Is it price? Is it something else in the data that would drive you to do so?

Yes. So we've -- because of our access to rituximab, the issue of switching has come up a fair amount between rituximab and OCREVUS, for example. And we've had patients switch between those 2 drugs are ready 3 and 4 times. I think it's a little bit of a disservice just because of the immunogenicity issues and things like this, but it's nice to have those options as well. We're dealing with another challenge now with biosimilars to rituximab. And now we've got Truxima in some centers and RUXIENCE and others and that kind of stuff. So I think we're doing somewhat comfortable in being able to switch. That decision, though, primarily is driven by access. Some insurance at this point have really kind of made a big difference. Is given the preference to us, then that infusion time becomes really important. And that's, I think, going to be a big differentiator for patients. And I think they would be much more likely to be able to kind of choose the option that gives them kind of the quicker infusions and that flexibility.

Excellent. Dr. Fox, Dr. Steinman, anything to add on to?

No, I think that's exactly what I would agree with.

I think over time, the access question to these preference of managed care will play a fair role in this, but most states do have regulations at stayed, at least for the commercial insurances, but if you're on a medication already established that the insurer cannot force you to make a change within that category to a different agent. They can go to a generic, but they cannot force a change to a completely different agent. So I think that we will have freedoms to make these decisions for our patients to either maintain their current medicine or to switch. But in terms of access that's going to be an open question, I think, over the years, and it may change during different years, I may have better access to one over the other.

And I would this a preference of choosing a medication that is approved. So I mean, unless you're kind of getting forced into using something that's off-label or something like that. And that's not frequently the case, especially for commercial insurers, there's still a big push to using something that has an approval label to it.

All right. Yes. I'll just -- as we wait for the next question to come in, I will just say that access has been something we've been super focused on. We've actually spoke to all of you folks about and to the investors that one thing we're looking at is how do we price this right to make sure we ensure as much access as possible. So that's something we're thinking about and working on. Next question.

Our next question today is coming from Matt Kaplan.

Congrats on the results. Just wanted to dig in a little bit more to maybe for Dr. Steinman, you had mentioned your impression of the primary endpoint, the annualized relapse rate of going below 0.1. How do you think about that? And how does it impact your kind of incorporation of -- potential incorporation of ublituximab into the treatment regimen for your patients?

Well, I think it's important in terms of feeling comfortable and telling individuals that this is something that has not been achieved in other trials. It's -- we don't like to compare one trial with another. That's the formal statement from us in academic medicine to our Chinese. Nevertheless, it's a very important barrier and since it's baseball season, I'd say it's akin to hitting 400. This hasn't been done before. Maybe others will succeed, but it's a really impressive result on the primary endpoint.

Okay. And then maybe for Dr. Fox since you have an infusion center associated with your business or your practice. You mentioned kind of top line overall use of CD20s to the planned question. But how do you think about incorporating -- potentially incorporating ublituximab into your practice, given its potential impact on the throughput in your infusion center?

The scheduling of patients' needs to have a little bit of wiggle room. When they come in, we want everybody to be on time. We want everything to be like clockwork, but especially in IV therapies, it may be difficult to get the IV working. So there are -- needs to be, I think, a sense that if you're not going to be stressing out the entire system on a day-to-day basis if you're running at near capacity. And we're all looking at other IV therapeutics that may be coming to the market for other disease states, like Alzheimer's and so on. And if your infusion center was purely 100% MS frankly, that'd be a little unusual nowadays. I mean, usually, it's neurology practices like mine, where it's a lot of different conditions and a lot of different biologic agents, therapeutics that are going to be given IV and so one that has the wiggle room to be able to fit multiple people in the chair in a day, really works out to everybody's favor. And so I think that having experienced nursing staff and so on is very important. But it does go to what Dr. Steinman said, the sense that the patient has of a relative calm and easing that this is not a therapy rought with worry. They're going to come in, they're going to get the treatment and they're going to go home or go to work or do whatever they need to do that day. And so I think the infusion suite going forward we don't know how busy it's going to be. We don't -- it depends on approval of other agents as well. But we know that this particular medicine is not going to be crushing to us in terms of personnel and time management issue.

I'll give 1 example as well. 3 years ago when OCREVUS or 4 years ago when OCREVUS came out, expanded sort of our access to be able to get these infusions. And our infusion center at the hospital had sort of -- I think it was something like 10 or 8 slots for long infusions a week. And you can imagine that the demand far outstripped that and we started to kind of have to really push out sort of when patients were able to not just get approved, but once they got approved, could be actually scheduled. So with the shorter infusions, it gives you flexibility, as Dr. Fox was mentioning, to be able to say, we can probably fit that person in. If things are going well and that kind of thing. We can usually get steroid infusions within that day or the next day because there are short infusions that you can kind of find little gaps to do that in. The long infusions are hard to schedule. So this is a big advantage from a scheduling perspective.

Our Next question today is coming from Josh Schimmer.

It's amazing times in MS treatment such transformation over the past decade. Quick question for the specialists. As you think about practice management considerations, would you be more likely to adopt ublituximab if it were priced above OCREVUS or if it were priced below OCREVUS in line?

Go ahead, team. So question is, would you like to see Ubli above or below OCREVUS and which one would you prescribe more based on that price?

I'm speaking for myself, I look at it from the standpoint of availability through carriers. And so if the start-up process for me is easy, then I know that I'm not going to realize what the true cost is to specialty pharmacy, to the insurer themselves, those arrangements are made behind the scenes. I'm not aware of it. I just know where it is in terms of the tier of availability for it. If it came out with a double step edit where they had to have failed 2 medicines before they could be put on this, that would be a big problem. And so I've been reassured to hear that TG has been very actively working on that in advance through strategies regarding pricing and tiering. I just want it available as first-line because if it's available as first-line to my patients, then I can think about it for anybody. I don't want to have to carve-out, oh, this is the only population that I can consider this drug. And I have good faith, a belief that that's exactly what's going to happen. The exact wholesale pricing on it doesn't mean very much to me, just is the access that matters to me.

To emphasize that point, I mean, when we saw OCREVUS initially get approved, right, the sticker price on it, the [indiscernible] was, I think, like $65 a year, which would have made each infusion about a little bit over $30,000. And then when the patient started to come out from our hospital infusion center, which is part of the reason why we can infuse it in our hospital. Patients were getting bills for close to $130,000. And so there is a disconnect between what the wholesale acquisition price versus the discount in rebating that happens. Another example was at the County Hospital where I go twice a month, the Tecfidera and Gilenya have very similar wholesale acquisition prices. And you could make the argument that there was a lot more hoops to jump and testing required to get on Gilenya than for Tecfidera. But we could not get Tecfidera as a first-line drug. And so we stopped even trying. And so I'm not sure what the prices were, I've been on the line with the directors, and these prices are kind of what the real prices are hidden to us. The trade secrets. And so all I can tell you is there was something really driving Gilenya use compared to Tecfidera use. And it made it kind of out of our hands as to which one we went with. And so I suspect that things like that will continue to be part of the factor with infusion.

Our next question today is coming from Chris Howerton.

I guess the first perhaps is directed to Dr. Steinman. Obviously, I agree, the ARR rate under 10% is obviously quite impressive. But I guess if we are going to compare across trials, how do you view the performance of the teriflunomide arm? Here in that it seems to be a little bit better, obviously, than the label and then maybe even better than it performed in other Phase III trials. Does that temper your enthusiasm at all for Batting 400, as you say? I guess, is one question. And then another question that I've gotten from investors out there is that is BTK inhibitors an approach that you think is interesting, is that something that would be viable in this landscape moving forward?

Well, let me answer the question. Again, I teach to Chinese at Stanford that we really don't like to compare trials. So I'm merely using the 0.1 is something that hasn't been achieved and Ubli surpassed it. One can do a lot of hand waving to elevate it or reduce its importance. It's a milestone, and that's about all I would say, maybe a better metaphor would have been instead of 400, the 4-minute mile that was first actually achieved by a neurologist. So I think that turning to Ubli, this is the first time that barrier has been broken. But let's -- your points are well taken and there's nothing really to add to that. What was the second part of your question?

The second part...

BTK.

Yes, yes.

Right. Well, we'll see how the data turn out will certainly be another opportunity to expand the therapeutic repertoire in MS, but we need to deal with what the actual data will show us.

Our next question today is coming from Mayank Mamtani.

Can you hear me okay, guys?

We can now.

Sure. Good congrats on the very strong data and long-time coming indeed, Mike. Actually, Chris asked both the questions that I had to. But if I may just build on the previous question, in terms of -- as we think about Dr. Alvarez, some of these biomarkers of disease progression, and we think about therapeutics that might be on the horizon. Like where do you see like -- it seems like we're really getting close to addressing a lot of the unmet need there for patients. Can you just maybe help us understand what sort of what's really left out there for any of these pipeline agents that are out there? And then, Mike, I have a follow-up question for you.

Yes, I'm happy to kind of take the stab at it. So I think there's still a lot of debate as to the right approach to treating MS. We talk about this use of higher efficacy therapies. And I think one of the nice things when you have a lot of options. Is there still a lot of discussion about which therapy is the right therapy for each person. So I think there's still knowledge to be gained about this. I think from a therapeutics from a relapsing MS perspective, the biggest challenges at this point are trying to improve convenience, the cost issues, some of these assets. But from an efficacy perspective, you can really kind of look at a patient now and say, we can stop the disease process. That's a little bit of a shortfall for progressive patients because we don't have great options for progressive disease. So we still have a huge unmet need there. We still have issues around reparative therapy. So patients that -- even after their first attack are left blind, left with -- unable to use an arm or a leg or something like that, that they -- what's that improvement going to look like. And so as we start to kind of see some of these improvement markers, trying to start looking at some of the that in outcomes for the studies becomes important. So I think there's still work to be done in the MS field. But I think definitely from a relapsing perspective, we're starting to see now that this baseline improvement in some patients, which is something that I don't know that we really thought was that possible with therapies that are strictly targeted at immuno system.

Yes, that brings up -- sorry, just back to the point on progressive disease. Now I think there was a prior question about BTK. What I've heard is that some of the BTK is -- some of the excitement is potentially in the progressive patients and the ability to potentially impact there. So I guess that's -- is that something that you've seen as well?

Yes. And maybe a follow-up sorry, Mike 2-part question for you. Like if you put this in context, how do you sort of take your LCM plan from here? And you try to go beyond -- above and beyond where maybe Roche and GSK are? And then also, just a side question I had for you, Mike. You did some recent market research, we did 2. Some of the toggles that may have changed now that you have the full data. And what does that mean from a market research standpoint and some access and other commercial considerations that you may have?

So wait on my question, did you guys get the second question on the -- to you guys? Mayank can you just repeat what you were asking to the panelists?

Yes. The question to the panelists are, like how do you advise TG to do the LCM going forward so that we stay competitive with the other CD20s and also with the BTKs kind of coming through the pipe?

LCM is life cycle management. Took me a second to actually get that one. Thanks, Mayank, for that one.

Apologize for that. Go ahead.

So the question is what kind of recommendations do you have for us in terms of things we can do to build into in MS.

I'd point out that the finding of the confirmed disability improvement. As Dr. Enrique said, there's a whole lot of -- Dr. Alvarez had said that there's several things that are going on that are not solved issues yet. And I think that, that is true. That we have done a great job at preventing relapses and increasing the number of people with no evidence of disease activity. But if we can look at biomarkers, whether it's no filament light chain or advanced MRI metrics or something else. And so the advice to a company is to be fluid with post-marketing research to be able to go back to frozen blood specimens and keep reporting on data that can confirm the findings of preservation of neural tissue and to keep the data available from MRIs to see if advanced metrics can be used for measurement of gray matter atrophy and so on. Because as this story evolves over time, what patients are going to be hearing, what the physicians are going to be hearing is the advances of science of really being able to predict the future better for who is going to be able to avoid secondary progression later on in life. And what we really would love to be able to say right now is that somebody has a 90% or better chance of avoiding secondary progression throughout their lifetime with MS. And we can't say that. I mean, even after an entire generation of therapeutics, we can't do that. There are still people who go into secondary progression, and we don't know why. We just know that there are certain risk factors that may make that more likely. So all of us are looking to, I think, be fluid in our ability to examine the data that's already out and then to be able to move it forward. That was a long-winded way of saying that we're not done yet with research on the agents that are on the market.

I think the other thing to that's come up recently, right, is this little thing called COVID. And a lot of people have kind of been hesitant to use CD20 therapies that have kind of paused their use of some of these higher efficacy therapies, because of concern for infections and things like that. So I think trying to understand as things come up like this, what the safety -- what the true safety is? How are people doing with COVID with these therapies? And I think Dr. Steinman has brought up the issue around -- we've seen people really actually do pretty well with COVID with these treatments. I think one of the things we're starting to kind of hear a little bit in some of our preliminary data is that the response of the vaccines for COVID with B-cell therapies is really pretty crappy. And so trying to understand what does that mean? What's that going to look like? Is that going to inhibit the use of these therapies? Are there strategies to try and improve that vaccination track record. Can we do boosters? Can we do double doses? Can we do other things like that. The strategies have been used for vaccines and other people, might be too much information, but I've had full shots for hepatitis B. And then finally serve converted. So I mean, it's -- their strategies to overcome these things. And I think that, that's going to be part of kind of the ongoing studies, I would imagine, to try and provide that comfort to continue using these therapies.

I'd just like to add on the last point and then go back to the first point that the easiest thing to measure in response to a vaccine is seroconversion. It's a lot easier to measure antibodies, but there's a whole other arm of the so-called adaptive immune system, the T cells. And the fact that so many people on anti-CD20 handled the stress test, as I call it, so well means that they may be getting immunity through that very important other arms. So I think that is an open question. I think that double dosing, giving a stronger set of immunizations and may prove effective. Again, the data will tell us. But again, people on anti-CD20s did not will to under the stress test. The other thing is, Dr. Fox is talking about someday, we're going to get to the point where we'll be very good with bioinformatics at predictive biomarkers, whether they're in the blood or imaging or in some other format. But I have to say that, although that's a long sought after need, and there have been great advancements in technology, we've done much better on expanding available therapeutics than getting to informative biomarkers that would answer the very question that we'd like to know. How is the disease going to go? What are my chances of ending up in a wheelchair and those are the kinds of things that we have to keep a frontal assault with more and more research to try to answer that. But again, we've advanced much more significantly in the realm of therapeutics than in predictive biomarker tests.

Our final question today comes from Ed White.

Can you hear me now?

Yes.

Well, congratulations, Mike, and thanks for hosting this call. All of my original questions were asked and answered. So maybe I can ask a somewhat loaded question, but assuming similar pricing and access, is there any reason for the doctors to start a patient on OCREVUS versus Ubli?

Go ahead, panelists. who wants to jump in.

I think the issue around the shorter infusion makes it a difference, right? We're seeing huge efforts by Roche and Genentech to try and shorten their infusion times that they've done in 3 or 4 different studies, because it's -- it helps. And this is still faster than they're faster infusions. They're looking at trying to do sort of a subcu infusion option, things like this. So I think there's differences that still mark out that it makes it hard to kind of say that they're exactly the same molecule.

Dr. Fox, any reason you'd ever use Ocre again? And is the loaded question?

Well, yes, it's a good question because if I see a new patient, very soon in the first appointment, I'll ask whether they know anyone with MS. And if they have a friend or a relative with MS, I want to know whether they've had a really difficult case or a more straightforward case, whether they've done well on their medicines or not because that predisposes the person to fear of the disease or fear of the treatment based on what's going on. And so if you're looking at the market leader, there's more likely that a person is going to say, I know somebody on OCREVUS if they have the bigger market share. And if that's a shortcut to having the conversation about, well, is that medicine right for you, then I think one of the biggest challenges when you have medicines within the same category is breaking prescriptive patterns of the providers. So -- but it's also enlightening the people that -- well, we have one that does everything that you've just talked about but the infusion time is faster, access to it is very good. So here's why you might think about this if they're thinking about it as new and improved, they want to feel at least confident about it. So is there a reason to use it? Yes, if the short -- if there's a reason to use OCREVUS, it's because the patient already knows people on OCREVUS. They've already gotten that word-of-mouth and there's a shortcut to talk about that medicine over the newer one.

I would like to now turn the floor back over to Mike to conclude the session.

Great. Well, that was a great session. I want to thank our panelists who are, as always, very well informed, astute and on point and appreciate the candor across the board. Thanks, everyone, for joining us today. It's a very exciting day, and we'll say again for us at TG. We're looking forward to getting out there and pushing forward on our BLA submission, which we're targeting for the third quarter. Everything is on target and moving forward. So again, I just want to thank everyone for joining us and again, particularly for our panelists for taking all this time this morning. Have a great day.

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