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

[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, and thank you all for joining us. I'm Jenna Bosco, the Head of Corporate Communications for TG Therapeutics. And we're excited to review with you all today the data presented at the ECTRIMS 2021 Congress. Before we begin, I wanted to remind everyone that we anticipate making some forward-looking statements based on our current expectations. These statements involve risks and uncertainties that may cause our actual results to differ materially from those indicated. For a description of these risks, we encourage you to review the disclosures on this slide and also in our latest reports filed with the SEC, which are available on our corporate website at www.tgtherapeutics.com. With that, let's kick things off with a quick review of the agenda. First, I will briefly introduce our external speakers. Then I'll turn it over to our CEO, Mike Weiss, to provide some opening remarks, following which, Dr. Steinman will review the ULTIMATE I and II Phase III oral presentation. And then Dr. Cree will review the MSFC Late Breaking ePoster. And lastly, we will open it up to a Q&A session. So first, I would like to welcome and introduce Dr. Lawrence Steinman, a Zimmerman Professor of Neurology & Neurological Sciences and Pediatrics at Stanford University and also the Global Study Chair for the ULTIMATE Phase III trials. Dr. Steinman has worked closely with us since we launched our MS program and is a member of the TG MS Steering Committee. Thank you, Dr. Steinman, for joining us. Next, I would like to welcome Dr. Bruce Cree, a Zimmerman Professor of Multiple Sclerosis and the Clinical Research Director at the University of California San Francisco. Dr. Cree served as an investigator on the ULTIMATE Phase III trials and has been an adviser and member of the TG MS Steering Committee. Thank you, Dr. Cree, for joining us. With that, let me turn the call over to our CEO, Mike Weiss.

Great. Thanks, Jenna. I just want to start off by thanking Dr. Steinman and Dr. Cree for joining us this morning, their time and for obviously working closely with us on our MS program. I'm going to be very brief. We've got 2 great presentations, and we want to make sure we have time for the Q&A. I just wanted to note that we're obviously very excited about these presentations. We're super-excited to share them with you with this call and make Dr. Steinman and Dr. Cree available for the Q&A. What you're starting to see from the MS program, we have a, I would say, a complete redo of the original presentation, but some additional information was provided in Dr. Steinman's presentation, which you'll see. But then you'll start to notice that with the MS functional composite data, we're starting to really drill down into the data. We have a lot of information, and we're working our way through it. So this should be a pattern that people could expect that over time, we're going to start to really drill down into a lot of these secondary and tertiary endpoints and the MS functional composite as we're going to see more detail on today. Otherwise, just a quick update on the MS progress that we're making, as I mentioned in the last fireside chat with Alethia of Cantor. We are really pushing forward building out the team. As I mentioned on that call, we've really brought in an all-star team from a number of the best companies that have been marketing and developing MS drugs. We're seeing great interest in coming to TG. The team is really coming together nicely. I personally have been spending a lot of time with that team, and I'm excited about everything that they're doing. So I think you should be comfortable that the MS program is building out in a very nice and gated path at this moment. So with that, I will turn the call over to Dr. Steinman, who is going to review the ECTRIMS presentation that he just gave, I think, earlier today.

Thank you very much. Let's go to the first slide. So good -- let's go to the previous one. Thank you. Good. I'm Lawrence Steinman. I'm speaking to you from California. So good afternoon to most of you. It's still morning here. The title of this presentation is Phase 3 Results of the ULTIMATE I & II Global Studies: Ublituximab Versus Teriflunomide in Relapsing Multiple Sclerosis. I'm often going to refer to ublituximab as ubli for the sake of making this smoother. Let's go to the next slide. So ublituximab is a novel monoclonal antibody targeting a unique epitope on the CD20 antigen on B-cells. It's glycoengineered for enhanced antibody-dependent cellular cytotoxicity and is administered in 1-hour maintenance infusions. Let's go to the next slide. So the ULTIMATE I and II studies are identical Phase III randomized, multicenter, double-blinded, active-controlled studies evaluating the efficacy and safety of ubli in patients with relapsing forms of MS. The patients were randomized 1:1 to receive either 450 mg of ubli via a 1-hour intravenous infusion every 24 weeks, following a day 1 infusion of 150 milligrams over 4 hours or 14 milligrams oral teriflunomide once daily throughout a 96-week treatment period. Next slide. The study objective and endpoints. The primary point in ULTIMATE I and II was the annualized relapse rate. Go to the next slide. This shows the geographic mix of patients. We can go to the next slide, please. So the study adherence was good with approximately 90% of randomized patients completing the 96-week treatment period across both studies. Moving to the next slide. The patient demographics and baseline characteristics were consistent for both ULTIMATE I and II and are similar to previous anti-CD20 pivotal studies in relapsing MS. Slide 9. So the primary endpoint, as mentioned, is the annualized relapse rate. In ULTIMATE I, the annualized relapse rate at 96 weeks was 0.076 in the ubli group compared with 0.188 in the teriflunomide group. For ULTIMATE II, the annualized relapse rate at 96 weeks was 0.091 in the ubli group compared with 0.178 in the teriflunomide group. As you can see, both were statistically significant with reductions of approximately 60% and 50%. Going to the next slide. The MRI Gd-enhancing T1 lesions showed that the reduction in the total number of Gd-enhancing T1 lesions for the ubli versus teriflunomide was approximately 96% in both ULTIMATE I and II, both statistically significant. The next slide, please. The reduction in the total number of new or enlarging T2 hyperintense lesions was 92% in ULTIMATE I and 90% in ULTIMATE II in favor of ubli, both statistically significant. Let's go to the next slide. Confirmed disability progression. The ULTIMATE disability analysis was pooled across the 2 studies. A very low rate of confirmed disability progression was observed in both treatment arms. The ubli group had greater than 94% of patients not reaching CDP for at least 12 weeks and also greater than 96% of ubli patients did not reach CDP for at least 24 weeks. Let's go to the next slide, please. Confirmed disability improvement. The ULTIMATE studies also examined the effect on CDI utilizing a prespecified pooled analysis. Ubli treatment significantly increased disability improvement confirmed at both 12 and 24 weeks relative to teriflunomide. Approximately double the proportion of patients achieved CDI in the ubli group compared to teriflunomide. The next slide. No evidence of disease activity. In further support of the clinical benefits, no evidence of disease activity was improved with the rituximab treatment. The results translate to a 3- to 4-fold increase in the proportion of patients achieving that and in favor of ubli. Slide -- the next slide, please. Looking at brain volume baseline to week-96. The percent brain volume change was analyzed from baseline to week-96 as a prespecified secondary endpoint. Interestingly, there was an acute increase in brain volume in the teriflunomide group observed during the first 24 weeks in both studies. And this phenomenon has been previously observed in other studies with teriflunomide. A post-hoc analysis of the slopes from weeks 24 to week 96 illustrates that there is no difference in the brain volume decline between the arms in ULTIMATE I, and the rate in brain volume decline was lower for ubli in ULTIMATE II. Go to the next slide. Continuing from the previous slide, this is a post-hoc analysis of the percent of brain volume change, we baseline to week-24. Let's go to the next slide, please. There was -- just go back to that slide, I'll just make a couple of more comments. There's no treatment difference between ubli and teriflunomide in ULTIMATE I in this analysis. ULTIMATE II ubli had less brain volume loss at week 96. These brain volume results are generally consistent with those observed for other anti-CD20 treatments. Now we can go to the next slide. Thank you. Looking at the multiple sclerosis functional composite data. Participants in the ubli group had a statistically greater increase in their MSFC score. Please note that you'll hear additional MSFC analysis from the ULTIMATE studies from the poster presentation coming up. Slide 18, adverse effects. Overall, the ULTIMATE studies reported a favorable safety and tolerability profile with no unexpected safety signals. The proportion of patients reporting any adverse events was approximately 88% for both the ubli and teriflunomide groups across ULTIMATE I and II. The most common reported AEs were infusion-related reactions referred to as IRRs, headache and nasopharyngitis in the ubli group. Let's go to the next slide. Serious adverse events. This slide summarizes the SAEs. SAEs were reported in 9.5% of ubli patients and 6.2% of teriflunomide patients. 3 malignancies were reported, 2 in the ubli group and 1 in the teriflunomide group. There were 3 total deaths which occurred, pneumonia, encephalitis, post-measles, infection and salpingitis and were in the ubli group. One was deemed possibly related to treatment. That would be the pneumonia. There were no cases of PML. Going to the next slide. The infusion-related reactions. More ubli patients experienced at least 1 IRR compared to the teriflunomide group who received placebo infusions. Most IRRs were mild to moderate, that's shown in gray and green, and decreased in frequency with subsequent dosing. Next slide. Looking at the proportion of patients with immunoglobulin levels below the lower limit of normal. Overall, the proportion of patients below the LLN for IgM, IgG and IgA were as expected for an anti-CD treatment -- CD20 treatment over a 2-year treatment period. Finally, the conclusions. Next slide, yes. In the Phase III ULTIMATE I and II studies, ubli met its primary endpoint of ARR and reduced MRI parameters compared with teriflunomide. A very low rate of disability progression was observed with ubli, with greater than 94% of patients showing no 12-week and greater than 96% of patients showing no 24-week CDP, although neither was statistically different from teriflunomide. In a pre-specified pooled tertiary analysis, ubli increased the proportion of patients with 12-week CDI and 24-week CDI. A significantly higher percentage of patients with ubli achieved NEDA and displayed improved MSFC scores compared with teriflunomide. Ubli exhibited a favorable safety and tolerability profile with no unexpected safety signals. And these data are being prepared for market authorization. So in ULTIMATE I or II, ubli, a 1-hour infusion demonstrated robust efficacy and a favorable safety profile that benefited relapsing MS patients. And I'd like to thank the individuals with MS who participated in the trial. Next slide. Now I'll turn the presentation over to fellow Zimmerman Professor at our neighboring institution, Professor Bruce Cree from UC San Francisco. Bruce?

Thank you very much, Larry. Great presentation and very exciting data. So I'm going to now drill down a little bit more into another measure of disability, the multiple sclerosis functional composite. I'll just take a moment to describe what the MSFC is. For those of you not familiar, this was a tool that was developed by Gary Cutter, a well-known biostatistician, who has been involved in MS research for decades as an alternate method of assessing disability. And just as the EDSS utilizes the neurological examination to develop a score, the MSFC uses 3 separate measures: 1 for upper arm mobility and dexterity, which is called the Nine-Hole Peg Test; another measure of cognitive performance, which is called the PASAT, Paced Auditory Serial Addition Test; and a third measure of walking, the Timed 25-Foot Walk. Now you might ask why were these measures developed for MS? And it was to address some of the issues having to do with the EDSS score itself, which has a number of features that make a challenging score to use in the context of clinical trials. And the EDSS actually was never really developed for clinical trials in the first place. It was a broad score originally developed by John Kurtzke to characterize what happened over the life of the individual with MS and was not really intended to be applied to clinical trials in the way that we have done. Because of that, there are some inconsistencies with the EDSS. There's a lot of interrater variability. The EDSS scale itself is nonlinear. In the earlier portions of the scale, it's really a composite scale. In the later portions of the scale, it's heavily dependent on ambulation. And ultimately on whether patients are capable of walking at all or whether they're bed-bound and whether they're capable of any forms of self-care. So it's a very interesting score, very usable for all kinds of research, but for clinical trials, it has some issues. And so the MSFC was developed to have several features. One, the measures in this scale are normally distributed, and they can be grouped together as a z score. That is ultimately what the MSFC is. It's a composite measure of those 3 scores, 1 of cognitive performance for the PASAT, the Paced Auditory Serial Addition score; 1 of upper arm function, which is Nine-Hole Peg Test; and lastly, 1 of ambulation, which is the Timed 25-Foot Walk. And the beautiful thing about these measures is they don't require a neurologist to perform these measures. They can be done by study coordinators. Next slide, please. So Larry has already described the background of ublituximab. I won't go into this any further. Next slide, please. And he's also described the baseline characteristics of this cohort, which are fairly typical for relapsing MS studies, mostly women around the age of 35, 36. Next slide, please. So here is the multiple sclerosis functional composite change. Now this score, because it can either improve or get worse, is reported in this way. Unlike the EDSS, which is grouped as either a worsening or defined either by worsening that is sustained or worsening that -- or improvement in the EDSS that is sustained, the MSFC simply looks at what happens at the start of the study and asks the question, has the score changed at the end of the study. And so that's what you're seeing here, baseline to week-96. There is no particular confirmation of change in MSFC. It's measured multiple times over the course of the study. And the question is simply, has it gotten better, has it gotten worse? And what you can see from both ULTIMATE I and ULTIMATE II is 76% to 89% improvement in this score, reaching statistical significance for both studies, favoring ublituximab over teriflunomide. And the least mean -- squares mean was used for this particular analysis. Next slide, please. Now looking at the individual components. This is the Nine-Hole Peg Test. And for those of you who haven't performed this test, what you have is a set of 9 peg holes and you take a peg from a dish and you put the peg into the hole. And the pegs look just like the pegs that you played on as kids when you played battleship, if you remember that childhood game. So you go ahead and move those pegs over from a dish into the holes. You have to get all 9 holes in place that they make a square, and then you take them all out and you put them back. And that takes a certain amount of time. And you do that twice with each hand, the nondominant hand and the dominant hand. And so here, you can see the change in the Nine-Hole Peg Test favoring ublituximab with an improvement in upper arm function, with teriflunomide doing a little bit worse, perhaps more so in the ULTIMATE II study. Next slide, please. And now looking at ambulation. This is the Timed 25-Foot Walk, which is exactly what it says what it is. It's well titled. It's how long it takes you to walk 25 feet. So if you or I were in the hallway, assuming that we are ambulating normally, it takes us roughly about 4, perhaps 5 seconds to go 25 feet in the hallway. In MS, of course, people slow down, and it often takes 6, 7, 8, 9 or even longer seconds to go down the hallway. Some people have to use a cane, some people have to use a walker to make it down the hallway. And this measure is really quite well translated into how far someone can walk, which is really what we want to know at the end of the day. Not only what their speed is, which is important, but the speed over a 25-foot distance correlates quite well with maximum distance in MS. What you can see here in ULTIMATE I was a stabilization of the Timed 25-Foot Walk, which worsened with teriflunomide, didn't quite reach the level of statistical significance in that study on its own. And in ULTIMATE II, an improvement in the Timed 25-Foot Walk with ublituximab, worsening with teriflunomide, and that result reaching a level of statistical significance. Next slide, please. And now looking at the Paced Auditory Serial Addition Test or PASAT. This is a challenging test where people have -- hear a string of numbers, and they have to add 2 numbers together and calculate the score correctly, as the numbers are moving by. It's quite challenging to do. You have to really attend carefully and perform that simple math in your head as you're listening at the same time. Difficult to do, but a very useful score for looking at attention and processing speed together. And what you can see here is no difference between teriflunomide and ublituximab in either the ULTIMATE I or ULTIMATE II study. Both scores improving in both trials in both groups equally. Next slide. So in conclusion, in the primary analysis of the Phase III studies, ublituximab proved superior to teriflunomide in terms of the MSFC. There were a number of improvements in terms of disability with respect to the MSFC as well as confirmed disability improvement. And I think it's important to take both of these measures together into context. I think one of the challenges with this study is because confirmed disability worsening was not met as a secondary endpoint. One of the critiques of these trials is that there isn't an effect of ublituximab on disability. And I would say that the data here in terms of both the MSFC and confirmed disability improvement argues against that. We didn't see worsening because worsening actually was quite rare for both treatment arms in the course of this study. And if you have very few medically relevant events, it's actually very difficult, if not impossible, to demonstrate a treatment effect unless you have very, very large numbers. And I think that's what would have been needed in this trial. I think we would probably have had to more than double the sample size with the rates of disability worsening that we saw in this particular patient population. And in MS, that's not uncommon. We often see variants in terms of disability worsening trial-to-trial. MS is a very heterogeneous disease, and disability worsening is the -- in terms of its measurement by the EDSS is the most heterogeneous of all those measures that we look at in MS clinical trials. So it can be quite challenging. So this is not the first time that we've seen a drug have potent effects on relapses, MRI endpoints and MSFC, but not need that disability outcome measure. So I'm going to conclude at this point. I think that's my last slide. I don't know if there are any others. I can see there are quite a few questions going on in the chat or at least communications in the chat. And so -- and I see one Q&A question that has shown up and turn things back over to our hosts. Thank you very much.

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

A couple of questions, I think, for the physicians. One, just talk a little bit about like how you would incorporate this into your practice in light of, obviously, OCREVUS being kind of the standard of care here. And like what kind of things would be appealing -- what profile would be appealing to you like maybe from an operational standpoint? Is the 1-hour difference versus the 2-hour difference meaningful? Another question is just talking about this CDI versus progression. Like can you talk a little bit more about other studies where it's occurred or why -- I may have heard -- I know you said maybe it's because of like smaller -- not large enough numbers. But have we seen this before with teriflunomide and stuff like that? Just with those 2 for now.

Larry, do you want to start?

Go ahead, Bruce. I'll chime in.

All right. So I think in terms of clinical practice, you mentioned something about OCREVUS being a 2-hour infusion. And I think it's important to understand that OCREVUS can be a 2-hour infusion for those individuals who don't have infusion reactions to OCREVUS. It is not a 2-hour infusion for the overwhelming majority of individuals. It's a full half-day infusion, sometimes longer for most people. Not everyone can be put on the rapid infusion process with OCREVUS. And that's, I think, a very important point here. So to have a drug that can be much more rapidly administered, and possibly after the first infusion is done, even administered at home, that's a personal point of speculation on my part, I think would represent an improvement in terms of care if all other elements were comparable. So I think that's an interesting distinction between these 2 products. So when we're administering OCREVUS, we have to deal with a lot of infusion reactions. Only experienced infusion centers can manage these infusion reactions. And I think an important feature of this trial that needs to be called out is the quality of the infusion reactions that occur. The infusion reactions for the most part with this study were mild elevations in body temperature or pyrexia. And I think if I were to use this drug in my personal practice, I would premedicate all the study participants with acetaminophen in the same way that was done with OCREVUS and is currently being done with OCREVUS. Not only do we use methylprednisolone and diphenhydramine, but we also use the acetaminophen as premedications. I think I probably would do that with this drug as well. And that is going to reduce the frequency of that initial infusion reaction considerably. When you have a CD -- a complement-mediated cytotoxic effects, the B-cells lies very rapidly. And they do so in a way where their internal contents are released into body tissues quite readily. I think that's part of the reason we see a lot of that scratchiness and itchiness at the back of the throat, people feel like their throat might be closing with the OCREVUS infusions. Of course, it's not. When we take a look, everything is widely patent. But it does result in delays. And we have to slow things down. We have to often administer more Benadryl. More Benadryl makes people more drowsy, more out of it. Sometimes you have to use additional cortisol as a rescue, and the whole process can be slowed down. And it is not uncommon for a OCREVUS infusion to take the better part of a day before patients can be discharged from the infusion center. So I think that's an interesting component of the OCREVUS infusion experience, which really is very different for ublituximab. Pyrexia being the #1 adverse event and one that I think can be easily mitigated, now that we know that, that's the event you think about. And that scratchiness and itchiness at the back of the throat, the hives, the cutaneous reactions, we see that far less commonly with ublituximab. Why? Well, I think it's because the B-cells are really being consumed by phagocytes and they are being digested within the phagocytes in the intracellular space so that their cytokines are not as easily released into neighboring tissues. And I think that's part of the reason we're seeing a different adverse event profile with ublituximab compared to ocrelizumab. So in summary, I think the AE profiles for these 2 products is sufficiently different as well as the duration of infusion that there is a competitive advantage of ublituximab over ocrelizumab. A lot of work is going to need to be done to establish that in clinical practice. But personally, that is my takeaway from having worked on both of these products and having extensive experience with use of ocrelizumab in my clinical practice.

I just want to emphasize a couple of the very cogent points that my colleague, Dr. Cree made. One is the difference in controlling the fever can be readily mitigated with the use of acetaminophen. Second, it has to be emphasized that for many busy people, whether they're young adults taking anti-CD20 therapy who have school to attend or jobs to get to, getting out of the infusion center in a short time allows the rest of the day to open up. It may not sound important to many of us, but it's intensely important to active people. And as we treat more and more people early in the course of disease, these are people who have very significant responsibilities on their shoulders. So that's a great benefit. The third point is that the glycoengineering may also be leading to the difference in these infusion reactions. Dr. Cree mentioned that the cytokines, those materials that cause the itchiness, scratchiness and fever are metabolized within cells that are there to do that, macrophages and polys. Whereas the glycoengineering, when it's absent, may lead to greater release out in the periphery. So those are points that follow-up studies can help to really nail down. But I think that the results are very different in favor of ease of administration for ublituximab.

Then there was a second question having to do with both CDI and CDP. And I think it's probably worth just going over what these measures are. So the EDSS score is a summary score of the neurological examination. And we define change by that score of a point up to the EDSS score of 5.5, and then a meaningful change is 0.5 point thereafter. So that 1 point change, that needs to be confirmed to certain interval afterwards, and clinical trials do that either at 3 or 6 months. Why do they need to do that? Well, because the EDSS score itself tends to bounce around, goes up and goes down. And so one of the goals was to try to develop a way of determining whether the EDSS score change was really going to represent a reversible change. Even with the 3-month and 6-month confirmed disability progression score, using a 3-month confirmed disability progressions for about half of patients who will experience that confirmed disability, will revert to their earlier EDSS score means that they have gotten better at the time of their next evaluation. With the 6-months confirmed disability measurement score, it means about 1/3 of those patients are going to get better. So it's a useful tool, but it is extremely variable. And this is one of the reasons that it's so hard to demonstrate an effect on using that tool as the only measure of disability in MS clinical trials. This is because disability doesn't change very much over the typical duration of an MS clinical trial. And irreversible disability is an infrequent event in relapsing MS patients, often requiring many more years to follow up to see that type of change. Remember, the EDSS score is a score intended to be used over the life of the individual. So for somebody who develops MS around the age of 30 is supposed to be using a scale over the next 40 to 50 years. MS clinical trial has been 2 years in duration. The scale is really not all that great for this particular application. And that's where a lot of the challenges with the EDSS come from. Okay. So all that being said, if you have a group of individuals, a population of individuals that you select that don't have frequent disability confirmed worsening scores at all, regardless of what their treatment is, whether it be placebo or an active comparator, if the group is not predisposed to have much worsening, it's going to be very difficult to show an impact of a particular therapy that you're using to compare either to placebo or to active treatment. And that, I think, is exactly what's occurred in this clinical trial. The rates of disability progression are lower for this study than for many other studies. They are lower for this study than, for example, teriflunomide compared to placebo. Of course, there's no placebo in this trial. And so that means that -- since we know that teriflunomide has an impact on disability, it's even harder to show an impact greater than that unless you have a fair number of events occurring. And that just didn't happen here. That's luck of the draw. We see this variability across trials all the time, and it can be a source of great consternation. But the critical thing here is not to over-interpret those results. This is not to say that ublituximab doesn't benefit patients with respect to neurological impairments. It does. That's proven by the confirmed disability improvement as well as the change in the MSFC. And those 2 measures are complementary and add to the understanding of the impact of teriflunomide on neurological impairments in relapsing MS.

I think just to emphasize again what Dr. Cree has said that as we drill down further into the results of this trial, there are some subtleties that are very encouraging, and the MSFC result is one of them. I also want to emphasize, as we drill down, the findings are very reassuring and make me optimist about ublituximab. But we don't have to drill down. If we go to the primary endpoint, the annualized relapse rate, a certain barrier was exceeded. And it was the first time that in one of these trials that the annualized relapse rate went below 1/10 of a relapse a year. And that's also very important news to be able to be in a room with an individual with MS and their family and to tell them that this is a very powerful drug in blocking those very much feared relapsing events. So both drilling down and looking at the big picture, both ways, there's very encouraging stories.

A quick follow-up, just in percentage, how many people actually can do a 2-hour infusion of OCREVUS in your practice?

In my practice, it's about 40% -- 30% to 40%. Most people are still getting the usual infusion. And that's with extremely experienced nurses at our infusion centers. Many infusion centers simply can't administer this drug effectively. And often CD20 antibody therapies are stopped abruptly before the infusion is completed, and the drug is wasted because of inexperience of infusion centers with use of this type of medication, I mean, outside of busy oncology practices that have experience with rituximab, of course.

The next question is coming from Matt Kaplan.

Just to drill down a little bit more and follow up on Alethia's question. You guys provided both -- provided good detail on how this impacts the patients in terms of the differences between OCREVUS and ublituximab. Can you help us understand in terms of kind of the practical nature of the differences between the 2 products? And how they affect your practice, perhaps in running an infusion center and thinking about those practical issues associated with that, not just from a patient's perspective, but maybe even from a nurse's perspective at an infusion center as well?

Well, there's going to be a lot of potential changes in the landscape with infusion centers, particularly those doing drugs for neurology, and it has nothing to do with the anti-CD20. It will depend on how crowded these infusion centers are going to be with another recently approved drug for Alzheimer's dementia. So getting patients with a quicker turnaround time in terms of the patient flow in the infusion centers may be an unexpected very important point that is trying to come up. It's hard to predict the landscape if the Alzheimer's patients are going to be in those infusion centers taking up a lot of the beds.

So I'll just make an additional comment here. Larry developed a drug for treatment in MS called TYSABRI. I don't know if any of you have heard about that one. It might be slightly before your time. This is a Biogen product that has been used extensively in treatment of MS. It's a 1-hour infusion, but done every single month. And that 1-hour infusion factored very favorably into many infusion centers' economic profiles. Why? Because you can flip that table pretty quickly. It's not easily fast food at McDonald's, but it's also not a multicourse sit-down dinner at Auberge du Soleil. So you've got something that you can administer rapidly. You get paid very well for that first hour of the infusion. Every subsequent hour, you get paid less and less. That's the way medical reimbursement works these days. The faster you get it done, the better economically it is for you. So I think there are some advantages there from a practical perspective. Ultimately, I think I alluded to this earlier, there's also potential for this drug to be used in the safety of someone's home. After that first infusion or a couple of infusions, the patient is tolerating the drug well and you know it can go in quickly. Why not administer at home? We're beginning to do that to some extent with ocrelizumab. But the infrastructure is not entirely there or complete at this point. And I think this is something that ublituximab can certainly leverage, at least in my personal opinion. That would be something that could be leveraged with this particular product.

That's helpful. And then just a follow-up for you, Dr. Cree, in terms of the multiple sclerosis functional composite scale. How often is this used in other trials or -- and also in practice? And with respect to the data that we're seeing now with ublituximab, can you help us compare and contrast what you've seen otherwise with MSFC?

Sure. So this scale is used all the time in MS clinical trials and, as I mentioned, an alternate way of assessing neurological function in patients that is different from the EDSS. And I described how it's different and how it can be administered. So pretty much all trials include this these days. Neither the EDSS nor the MSFC really are used in clinical practice. In clinical practice, you just don't have time to mess around with these things. Maybe half an hour for your patient's appointment where you have to take the integral history, perform some form of the neurological examination, make -- review the MRI scans, relative -- relevant laboratory data and then come up with an assessment and plan. And that pressure is just too intense to -- well, it's just too intense. But it's too intense to incorporate these additional standardized measurements such as the MSFC or the EDSS. Most people don't calculate EDSS scores when they examine their patients. So could it be done? Yes. Will it be reimbursed? No. Every time you invest time and effort into something that you're not getting paid for, you have to kind of be worrying a little bit about what you're really doing and what you're trying to accomplish. So I think both of these are research-based measures. They're very useful for understanding the impact of a drug on a disease state. They are the key components of the primary literature that we, as providers, look to, to understand what a drug does and what its benefits are. But from the FDA's perspective, with respect to disability, the only measure they are concerned about at this point is the EDSS score. That is number one, first and foremost. Timed 25-Foot Walk is being used, and the FDA have approved one medication based on the Timed 25-Foot Walk performance, and that's AMPYRA, which was specifically intended to have an impact on the timed 25-Foot Walk. So they did accept it for that one particular study. So we see an effect here, and Timed 25-Foot Walk is encouraging. Remember, with the EXPAND trial with siponimod, we saw an effect on the EDSS, but we didn't see an effect in the Timed 25-Foot Walk. So all depending on how the study is conducted and the nature of the population under study, sometimes you get a hit on one of these scores and not on the other. So that's something just to sort of think about and factor in. And I think -- the FDA is wise in this, even though it may be part of your statistical analysis plan, that specifies that we're not going to look at anything else if you don't hit your secondary endpoint. The FDA always looks at the totality of the data. And many drugs have received approval even after not meeting their primary endpoint. It's statistically providing that the additional supplementary information was all going in the right direction. There is a Q&A question here, I don't know if our hosts want to follow up on this, from [ Robert Short ] having to do with the safety profile.

Yes. I think we're going to go through the Q&A from live call. And if we have time, we'll come back to any...

Thank you, Michael.

Our next question today is coming from Josh Schimmer.

Great. Can you provide a little bit more context for the Grade 5 infection that might help establish that these events don't really reflect excessive B-cell depletion compared to other CD20 antibodies?

Josh, I think to answer that very good question, we'll have to drill down on the data and look at the timing of when the Grade 5 infection occurred in relationship to what the actual count was, how far away from the actual depletion, whether there was repletion going on in order to make a careful evaluation and then frame it across studies with when other things were seen. Remember, it's a dynamic situation that counts fall and they slowly replenish. So I don't have an explicit answer on that, but the degree of depletion wasn't very much different than the other anti-CD20s, particularly ocrelizumab. So it's hard to make an assessment without getting more granularity on what those actual -- the timing of those events.

I'd like to just make a couple of comments about some of these. I mean one was a measles encephalitis. Another was a patient who had an ectopic pregnancy and underwent a surgical procedure and then died, I think, of septic complications following that operation, and there was abscess at the site of the surgery. That doesn't sound very B-cellish to me. That sounds like a botched surgery with a bad outcome. So very hard for me to implicate use of CD20 regardless of the state of B-cell depletion when you've got a purulent abscess following an operative procedure in the abdominal cavity. So that's -- that, to me, just doesn't seem very plausible. And then the encephalitis, any measles infections really are extremely uncommon in populations that are generally vaccinated, right? We just don't see it very frequently. If you're vaccinated against measles, you don't get measles encephalitis. But if you're not vaccinated, you can, and it can be a catastrophic infection. Now whether B-cell depletion factored into that, I think, is -- remains to be determined. But at least, I don't -- my interpretation there would be that it would be very unusual for B-cell depletion of any kind to result in an active measles infection in someone who's been previously vaccinated. So that needs further follow-up. And then lastly, the pneumonia, I mean, who can really say, right, it's pneumonia. Patient died very quickly of pneumonia. There were other comorbidities that might have factored into that. This was all pre-COVID, of course, so we can't blame it on COVID. But these things unfortunately do occur. All 3 deaths occurred in the Ukraine. And nothing against the Ukraine or anybody of origin from that part of the world. My mother, in fact, is from Odessa. But in clinical trials, Ukraine is frequently a site of AEs and serious AEs. And I don't know why that's the case. I think there may be some differences in the way health care is delivered in the Ukraine or perhaps the general health of the populous under study. So it's something for us to kind of think about and keep in mind as we do these global clinical trials.

Our next question today is coming from Chris Howerton.

Great. I think maybe just 2 questions from me. One would be the subcutaneous CD20 ofatumumab has kind of gotten off to, at least from our side, the investment community, a slow launch. I guess, have you guys used that in your practice to date? And I think one of the comments that you made was that maybe in-home infusions could be a possibility. So I guess, curious to hear your thoughts on the subcutaneous presentation within that setting as well. And then a follow-up question would be is that I've had a variety of question or conversations with neurologists over the last year or so. And there's been at least a sentiment of trying to use more potent CD20 like therapies earlier in the treatment paradigm. I'm curious if that's still a trend in -- that you guys are seeing and would hope to see in your practice moving forward?

As far as early intervention, almost any disease, whether we're talking about relapsing MS or cancer, early intervention with a definitive and generally safe drug is going to be more effective than delayed intervention until somebody shows me a counter example. So I think it's a trend that will continue to grow. There's been quite a few comments in the questions about the possibility of home-based infusions. And again, I think the landscape might be in flux right now, and we'll see what the demand is on infusion centers. But as far as these rollout strategies, perhaps Mike Weiss can give some more context than I can.

I possibly could, but...

I was going to say I don't know if Mike is going to go for that, yes.

Yes. The home infusion thing, that's just my personal opinion. It is not a statement having to do directly with TG Therapeutics. So I did ground that by saying this is my opinion, which I think I'm allowed to do here, right? It's what I would like to see. We've got Mike Weiss on the call. He's hearing that from me. So who knows what TG is going to do, right? But they've got their advisers, their trusted advisers on the line here, and they're saying, yes, I think this is a good drug. And I think we could administer it safely. And following that first infusion or 2, we could potentially even administer it at home. That's an idea. It's not a policy, and it's not something that I think you have to -- you can take to the bank. I mean I think this is something that's a concept and might be -- might make life easier for our patients, which really is ultimately what we want at the end of the day. I can't agree more with what Larry said about intervention of these types of products early in the course of the disease. And we're actually conducting a clinical trial with another anti-CD20 early on in the course of MS right after that very first clinical attack within 90 days of symptom onset. And what we're seeing is really remarkable stabilization of all measures of MS in these patients, which goes along with what you would think with the drug that has greater than 90% efficacy in terms of clinical attacks and radiographic lesion formation. So we'll see ultimately whether that trial can produce the results that we want to see, which is eradication a of abnormal intrathecal synthesis of ganaglobulins, which is currently our only biomarker for multiple sclerosis to date. And hopefully, we'll have information on that to present down the road. But our hope is to be able to, early in the course of the disease, ablate the underlying disease process. I think this is a very interesting strategy, could potentially be applied by other anti-CD20s and is an area of intense and very active research. In terms of ofatumumab, yes, I think the launch has been very slow with ofatumumab to the considerable consternation of Novartis. I'm sure they would like to see much more use of this product. And I think they're going to see increasing use of it. The drug can be administered quite readily at home. It is -- like many Novartis products that have been launched in the past, there are great numbers of access issues that are occurring right after launch. So we're seeing step edits and flat out denials of insurance. These are all things that have to get worked out before products get launched, not after, at least in my opinion. And they really drag down the application of a particular medicine. So if you're a provider and you reach for something on your shelf and you grab that thing and say, "Okay, I think this is a good fit for you," and you prescribe it to your patients, right now, we have absolutely no way of knowing whether the third-party payer is going to allow that to move forward or not. So we fill out our forms dutifully. We send them on in. And then the whole process just gets rolled up into a very difficult Gordian knot. And often, we are dealing with third-party payers who don't want to pay for new drugs. And you would think that with KESIMPTA, it would be a cheaper drug to administer than OCREVUS. Why? Well, because there's no infusion center, you're not paying for nurses, et cetera. And that stands to reason. But ultimately, at the end of the day, that average wholesale price has nothing to do with the actual price of the product. All of this is done through middlemen. Nothing against my good friends who work over at McKesson. But they use a variety of very interesting strategies to have with loss leaders and so on to sell a panel of products to a third-party payer. And we're not privy to any of those backroom negotiations. It's all absolutely okay. And so, I guess, we just don't know how easy it is going to be to administer KESIMPTA to our patients. And I think that's one of the reasons that the product has really lagged. There are a lot of challenges with getting drug to patients. If those challenges can be -- if those roadblocks can be removed prior to the launch of the drug, you have a much better chance of success. So that's something for Michael and colleagues to think about as they are preparing for the launch of ublituximab.

Following on what Bruce said. The potential for home infusions will depend on the experience and the qualifications of the person going to the home. It's -- for most of us, it's much easier to contemplate not having to go to the doctor and navigate trivial things like the parking barriers and getting to the right place. But having said that, there is a large group of specialists who, including anesthetists, who are interested in doing this kind of work. One other comment from Bruce's description of the study of early intervention with an anti-CD20, the hope that I would have would be something akin to what has been seen with rheumatoid arthritis with the anti-TNF. No one is in a wheelchair anymore who has been recently diagnosed with rheumatoid arthritis. Whereas a generation ago, many people faced ending their lives for decades in a wheelchair because of that disabling disease. And maybe we'll be able to see the same thing in our patients with multiple sclerosis with early intervention with potent agents like the anti-CD20s like ublituximab.

Excellent. And I think, Dr. Cree, just for your edification, Mike and team have very much emphasized access and pricing as a key focus for them in terms of the commercial launch.

That's great. That's great.

Well, that message has got across, Chris. Thank you for mentioning that.

We are all smiles here.

Our next question today is coming from Graig Suvannavejh.

I've got 2 and they are both for the doctors. First, just on the choice of teriflunomide in the study, just wondering how -- for those who aren't maybe MS specialists on the call, but how should we be thinking of teriflunomide as a drug in terms of how it's being used right now and with this data, obviously, it's very powerful data? But can you just give us a sense of how much patients are actually using teriflunomide and the strength of the data with teriflunomide as a comparator? And then my second question is really more about COVID and trying to get a sense of how much COVID has, over the past 1.5 years or so, impacted your practices and maybe patients' ability to get treatment, whether you want to use qualitative comments or quantitative comments either would be welcome.

I'll start out with the response about COVID. It's a changing landscape. And one thing, if possible, it would be good to have immunization status completed before initiation of therapy. Certainly, people are able to get immunized after receiving anti-CD20, but the response isn't as robust as in comparator group. So all things being equal, getting the -- if it's an RNA vaccine, the 2 infusions before beginning therapy is a sensible idea. We have recommended it for other therapies to make sure that a live virus is given before getting a potent immune modulator. But for the RNA vaccines, I think it's still a good idea, although there -- we need more data on that. As far as teriflunomide, I think it's certainly in a totally different category of drugs based on its comparative efficacy as we see in this kind of head-to-head situation with an anti-CD20.

Yes, I'll just add a little bit more about the teri comparator. When you do a trial like this, really what you want to do is a placebo-controlled trial, right? But you can't today because we have so many therapies available for MS. So you have to use an active comparator for ethical reasons. So you're going to pick an active comparator that you think you can demonstrate superiority on. And so the entire study is constructed around a concept that you were going to show greater efficacy beyond a certain extent, factoring in individual variability. And that's how we set up the sample size calculations in trials like this. So you have to then pick what your competitor is going to be? Well, OPERA used Rebif, right? Ozanimod used Avonex. So these studies have traditionally picked platform therapies that are injectable and have shown superiority over injectable therapies. Well, injectable therapies aren't used so much anymore these days. I guess there's still some [indiscernible] use and some interferon use. But by and large, people have moved over to either oral therapies or infusibles. So in the infusible, you've got another anti-CD20, you can't really expect to show superiority there. And you've got natalizumab, TYSABRI where you're doing infusions every month. And so that's going to be a challenge to demonstrate superiority there, too, because TYSABRI is quite effective. So you're left with the orals. And so it gives you a choice between fingolimod, also quite effective; dimethyl fumarate, perhaps a little less effective; and then teriflunomide, perhaps even less effective after that. They all work. They're all approved. What are you going to do? Well, the more effect of a drug, the harder it's going to be to demonstrate efficacy. So you're going to pick the least effective of those that you think can be still safely used in treatment of the MS. And so that's why teriflunomide has been used for both the [indiscernible] and ULTIMATE clinical trials. It makes good sense to go after teriflunomide because it's a reasonably well-tolerated oral therapy that has an effect on both disability as well as relapses and MRI outcome measures. So that's the simple rationale there. You're going to go after something that's going to keep your sample size containable.

We've reached the end of our question-and-answer session. I'd like to turn the floor back over to Mike Weiss for any further or closing comments.

Sure. So I just want to thank both Dr. Steinman and Dr. Cree for an excellent session. I remained quiet. I did get the message on the home infusion, Dr. Cree. So it's something that we actually have talked about internally, and we will continue to evaluate if it's a feasible alternative or option, which I think it actually is possible to make it an option for folks. So we are working on it, and I will personally keep you updated on our progress in that area. So thank you for your thoughts there. There was one lingering question in the queue about the effects of T cell subsets. We did a very robust look at all the lymphocyte subsets in the Phase II trial, and there was no impact on T cells in that study. So no effect on T cells with ublituximab. And that's what one would expect, only CD20-positive cells would be impacted by ublituximab. Again, I want to thank everyone who joined us today. And again, great session. And as noted, we will continue to drill down into the data and look at some of these secondary and tertiary endpoints to give a lot more color around the impact of ublituximab. But overall, I think we're certainly very excited about the profile. And I believe that Dr. Cree and Dr. Steinman, I don't want to talk for them, but based on their comments today, I think they have a positive opinion of the drug as well. So with that, I want to thank everyone for joining us, and have a great day.

Thank you.

Thank you, guys. Very much appreciate it.

That concludes today's webcast. You may now disconnect your lines, and have a wonderful day. We thank you for your participation today.