Hello, and welcome to the Atara Biotherapeutics conference call. At this time all participants are in listen only mode. A question and answer session will follow the formal presentation. As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Eric Hyllengren. Please go ahead. Thank you, operator. Good morning, everyone, and welcome to Atara's ATA188 data conference call. Earlier this morning, we issued a press release reporting updated two-year data from our ongoing phase I open label extension study of ATA188 and new magnetization transfer ratio imaging data being presented at ECTRIMS today in an e-poster. This press release and the slides we will be presenting during this call are available in the investors and media section of atarabio.com. Joining me on today's call are Dr. Pascal Touchon, President and Chief Executive Officer, Dr. Jakob Dupont, Executive Vice President and Global Head of Research and Development, Dr. AJ Joshi, Chief Medical Officer, Utpal Koppikar, Chief Financial Officer, and Dr. Doug Arnold of Montreal Neurological Institute, McGill University, and NeuroRx Research. We would like to remind listeners that during the call, the company's management will be making forward-looking statements. Actual results could differ materially from those stated or implied by our forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's press release and the company's SEC filings. These statements are made as of today's date, and the company undertakes no obligation to update these statements. Now, I'd like to turn the call over to Pascal. Pascal? Thank you, Eric, and thank you all for joining us this morning. As Eric noted, earlier today, we issued a press release reporting exciting MTR imaging biomarker data and updated phase I open label extension clinical data presented at ECTRIMS this morning for ATA188, our allogeneic cell therapy candidate for the treatment of multiple sclerosis. Before we get to this exciting ATA188 data, I would like to reiterate Atara's differentiated approach to allogeneic cell therapy that is described on slide four on our new deck. Atara allogeneic T-cell platform relies on leveraging the specificity of Epstein-Barr virus T-cells from donors and partial HLA matching to optimize safety and persistence without the need for TCR or HLA gene editing. Most other allogeneic cell therapy under investigation require TCR or HLA gene editing to limit alloreactivity and potentially confer sufficient safety, expansion, and persistence characteristics. Atara has treated so far more than 300 patients with tab-cel and ATA188 or clinical stage EBV-specific allogeneic T-cells with no significant safety signals to date. In addition, our portfolio of next generation CAR-Ts, which are based on the same EBV T-cell technology, requires minimal genetic modification for CAR insertion through gammaretrovirus vector, leveraging an approach that has no documented oncogenic or chromosomal issues. We believe that retaining the native T-cell receptor rather than gene editing out the TCR will potentially lead to better product for patients in terms of safety and persistence. Hence, we look forward to the continued development of our programs to deliver safe and effective allogeneic cell therapy to patients in need. Now on to ATA188, our potentially transformative therapy in progressive MS. I will hand the call over now to Dr. AJ Joshi, our Chief Medical Officer, and Dr. Doug Arnold, who will discuss the exciting ATA188 data presented today at ECTRIMS. AJ? Thank you, Pascal. Moving on to slide nine, I'll start by giving a brief background on ATA188 in progressive MS, which I won't review in great detail. Today, we'll describe results from part one of a phase I/II study, which evaluated safety and potential efficacy of ATA188 in adults with progressive MS. As a reminder, efficacy from the 12-month dose escalation portion were previously reported. Recall, a higher proportion of patients demonstrated sustained disability improvement, or SDI, when treated with higher doses, and that was largely driven by a sustained EDSS improvement. On slide eight is a brief reminder of the study design, for which the endpoints included assessment of sustained EDSS improvement, SDI, timed 25-foot walk test, and as an exploratory endpoint, magnetization transfer ratio, or MTR. The phase II portion of the study is named EMBOLD. EMBOLD is a randomized placebo-controlled study where the primary endpoint is percentage of patients with sustained EDSS improvement at 12 months. Moving on to slide nine, we have a reminder here of the definitions for sustained EDSS improvement, which is really clinically meaningful EDSS improvement compared with baseline, measured at two consecutive time points. Also on the right, we describe MTR as a MRI marker of myelin density, which Dr. Arnold will cover in more detail in a few minutes. On slide 10, we have a schematic of patients evaluated in part one of the dose escalation portion and open label extension of the study. Our total safety population was 25 patients. One patient came off study early because of an MS flare seven days after dosing. We have 24 patients in our overall efficacy evaluable population. On the left-hand side, you're seeing the patient disposition for the 12-month phase I dose escalation, and on the right-hand side is the OLE portion. The first two sets of boxes where it says yes or no indicates whether the patient achieved SDI during the 12-month dose escalation. Of the 24 patients, seven achieved SDI and 17 did not achieve SDI during that timeframe. If you move to the next two sets of boxes, it shows which of those patients continued into the OLE. In the top set of boxes, of those seven patients who had SDI, one patient did not enter the OLE, and that patient happened to be one of the EDSS improvers. The remaining six did enter the OLE. In the bottom set of boxes, 17 patients did not have SDI in the first portion of the study. 12 of them entered the open-label extension and five did not. That gives you 12+6 patients who entered the open-label extension study, for a total of 18 patients. Of the six who achieved sustained disability improvement and entered the open-label extension study, we provide the breakdown here. Four had achieved it by EDSS and two had done so by timed 25-foot walk test. At the bottom of the panel on the right, of the 12 patients who did not achieve SDI and entered open-label extension, two developed SDI during the open-label extension, both developed it by EDSS, and one also had improvement in timed 25-foot walk test. Of the 10 patients who did not achieve SDI and entered the open-label extension, we do continue to monitor these patients as the majority of them have stable EDSS without progression. Moving to slide 11. This is a text summary of a previous slide. Overall, nine patients achieved SDI either in the first 12 months or in the open-label extension. Of those, seven were EDSS improvers. Of the eight patients who enrolled in the open-label extension study and achieved SDI at any point, all of them maintained improvements at all subsequent time points except for one patient. The median time of follow-up over which the SDI was sustained was 18 months. Moving to slide 12. Many of you are familiar with this slide detailing the clinical results for each patient who had SDI. The good news is we've added even more green boxes in the later time frames. Now you'll see that the latest patient with disability improvement is up to 33 months and doing well. That's patient H, who didn't develop improvement in the first 12 months after receiving the lowest dose of ATA188. Returned at the 21-month time point for redosing at the higher cohort redose, and based on that, achieved both EDSS and timed 25-foot walk improvement relatively quickly, and now has a full two-point EDSS improvement and has maintained both EDSS and timed 25-foot walk improvement at all subsequent time points. In fact, if you look down the table, all but one patient achieving SDI maintained disability improvement at every subsequent time point. This one patient is patient K, who developed EDSS improvement at the 12-month time point, confirmed at 15 months, and unfortunately experienced an MS relapse six months after their redosing with ATA188. That patient's EDSS returned to their original baseline. Moving to slide 13. These are the patients who did not have EDSS improvement. What we're looking at is how many maintained a stable EDSS score. As we've mentioned before, a therapy that could maintain EDSS stable in PMS would be considered a transformational therapy. As you can see on this chart, seven patients maintained their EDSS score and only three declined in the open-label extension. Overall, the vast majority of patients have either improved or maintained disability status over the course of the phase I and open-label extension, which we're quite enthusiastic about. Moving to slide 14. On safety, the longest observation for patients is out to 39 months. With the open label extension, we're now getting into an extended observation timeframe with multiple redosings. We continue to see a very strong safety profile. We see nothing notable since the last time we reported out data at the Charcot Lecture. As a note, there was one patient who had a fall, which can be common with MS patients. That was considered unrelated to treatment. I'll now hand over the call to Dr. Doug Arnold, who will walk us through the new MTR data for ATA188. Doug? Thank you very much, and hello, everyone. I'm going to present new MRI results consistent with repair of myelin in subjects taking ATA188. If you look at slide 16, I should perhaps remind you that myelin forms a sheath around nerve fibers that's important for their function and for their survival. Magnetization transfer ratio, or MTR imaging, is a special form of MRI scan that is specifically sensitive to myelin. Changes in MTR are a marker of changes in myelin density in the tissue. As such, increases in MTR can reflect remyelination and decreases in MTR can reflect demyelination. Previous studies have shown that there's an association between decreases in MTR and increases in disability. We believe that MTR is important, as it may be reporting on the biology underlying EDSS improvement. In this study, changes in MTR were assessed in unenhancing or chronic T2 lesions, as well as in normal-appearing brain tissue. Normal-appearing brain tissue, of course, is not completely normal, but it's more subtly affected by MS. If you go to slide 17, this shows that the changes in MTR were assessed at six and 12 months and compared between subjects who showed sustained disability improvement and those who did not. Moving to slide 18, the left half of the slide shows MTR changes in unenhancing or chronic T2 lesions. Patients with sustained disability improvement showed increases in MTR in chronic T2 lesions compared to patients who did not. This is both at six months and at 12 months, and is in contrast to the natural history of MTR changes, which we expect to, under normal circumstances, to just decrease over time. The right half of the slide shows changes in normal-appearing brain tissue, where the abnormalities in myelin are very subtle. The two panels show the relative increases in MTR were also present but relatively smaller, although still suggestive of remyelination. If we move to slide 19, this slide shows the relation of changes in MTR to changes in EDSS, the disability score. Again, the changes for the unenhancing or the chronic lesions are shown in the left half. There's a moderately strong correlation between increases in MTR consistent with remyelination and decreases in EDSS. That is disability improvement. There are similar but smaller changes seen in the right-hand side of the slide in normal-appearing brain tissue, which, as I said, had much smaller abnormalities to begin with. In conclusion, the updated OLE results show a sustained clinical benefit, evidence of possible remyelination in patients with sustained disability improvement, and that ATA188 appears to be safe and well-tolerated. Moving to slide 21, the data suggests that patients on ATA may achieve sustained disability improvement at a higher rate and for a longer duration than would be expected based on the natural history of progressive MS. The MTR data provide evidence that remyelination may be driving the sustained disability improvement. Of course, although encouraging, these results need to be confirmed within a larger randomized placebo-controlled study, which is currently ongoing and enrolling. Thank you very much. Thank you, Doug. I will now hand over the call to AJ to provide a summary view of both the clinical and MTR data. AJ? Thank you, Pascal. Moving on to slide 23. Here, in the phase I study, an open-label extension for ATA188, what we've seen thus far is that treatment with ATA188 led to a sustained EDSS improvement in some patients, suggesting a possible reversal of disease progression. As we're showing on this slide, we've seen sustained EDSS improvement for seven patients at different starting points on the EDSS scale. Importantly, these patients are reversing their disability and making significant gains in function. For example, patient F has gone from needing a walker to just needing a cane at 24 months. Patients C and G have gone from needing a walking aid at the beginning of the study to now 24 months later, being able to walk a few hundred meters unassisted. Patient H has actually improved his or her EDSS score by two points at 33 months, and patient E has gone from a 5.5 EDSS score all the way down to a 3 EDSS score at 30 months. Three essentially means no walking impairment. These data are very exciting and have the potential to transform how we treat progressive MS. Moving on to slide 25. As Dr. Arnold just presented, for the first time, we're showing for the seven patients with sustained EDSS improvement, we're also seeing a statistically significant increase in MTR in unenhancing T2 lesions at the 12-month timeline, and this is suggestive of remyelination in those same patients who are showing physical improvement in the EDSS. In addition, we see that there's a positive trend towards an increase in MTR for normal-appearing brain tissues versus baseline at 12 months for those same seven patients who have sustained EDSS improvement. Overall, we believe that these increases in MTR may be suggestive of remyelination and support the potential biologic basis for clinical EDSS improvements observed with ATA188. On slide 26, onto the summary of what we've shown today. Updated results from the ongoing OLE demonstrate continued safety and tolerability of ATA188, with the longest followed observed patients receiving up to three annual treatments and up to 39 months of follow-up. Sustained disability improvement with ATA188 was driven by sustained EDSS improvement in most patients, and disability improvement was maintained at all subsequent time points in all but one patient. Patients who were treated with ATA188 may achieve SDI. Specifically, sustained EDSS improvement at a higher rate and longer duration than would be expected based on the natural history of progressive MS. Patients who achieve sustained EDSS improvement with ATA188 at any time in the study versus those who did not, showed greater increases in MTR from baseline at 12 months, which may be suggestive of remyelination. In general, an increase in MTR was associated with improvement in EDSS scores. These MTR data provide evidence that suggests remyelination may be the biological basis for the clinical disability improvements observed with ATA188. In summary, we're very excited to present these data to you today, and we're looking forward to future updates as we continue to progress with our phase II RCT, EMBOLD study. I'll now hand the call over to Pascal to close our prepared remarks, and share next steps for ATA188. Pascal? Thank you, AJ. These data are truly exciting and build our conviction that ATA188 has the potential to change significantly the life of many patients with MS. We believe that ATA188 has indeed the potential to be a transformative therapy for patients in progressive MS with a multi-billion dollar revenue opportunity. If ATA188 is effective in progressive MS, it might also bring significant benefit to patients in relapsing MS, which could further expand its revenue opportunity. On the manufacturing front, Atara has demonstrated the possibility for a manufacturing platform to support a biologic-like cost of goods manufactured or COGM at commercial scale, where in bioreactors, we could be able to manufacture up to 20,000 doses of ATA188 from just one leukopak from a healthy donor. Looking ahead, our phase II EMBOLD study is ongoing and enrollment is progressing well. As a reminder, the interim analysis of ATA188 is planned for the first half of 2022, and meanwhile, our ongoing discussions with large pharma partners are generating a high level of interest. Finally, I'd like to offer sincere thanks to our staff at Atara and to the patients who are participating in our trials of ATA188, their families, the investigators, and the support teams at the clinical sites. I would also like to extend our gratitude to Dr. Arnold for joining us on this call today, and also to our academic partners at QIMR in Australia who have helped us bring ATA188 to patients. Thank you. I now turn the call back to the operator to begin the Q&A portion of the call. Operator? Thank you. We'll now be conducting a question and answer session. If you'd like to be placed in the question queue, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing star one. One moment please while we poll for questions. Our first question today is coming from John Newman from Canaccord Genuity. Your line is now live. Hi, guys. Good morning. Congrats on some really interesting follow-up data here continuing to show very nice efficacy. Just had a few questions. The first one is, could you comment on how magnetization transfer ratio has been used with other therapies in MS? Also curious how much longer you'll be able to follow patients in the open label extension? Finally, if you could just remind us of the dose for ATA188 in the randomized phase II study? Thank you. Thank you, John, for your question. I think the first one will be for Doug, I guess, how MTR has been used. Yeah. With other MS therapies. MTR has been around for quite a while, but it has a relatively limited use in multi-center clinical trials for technical reasons which needed to be solved before it could be applied on all the different scanners that are present at all the different clinical sites. This has been available for several years now, and MTR has been used in a small number of clinical trials of different therapies. The bottom line is that in some of these therapies, I won't go into all the specifics, but with some therapies, we have seen a slowing of the decrease, the expected decrease in MTR in normal appearing brain tissue. It's unusual to see an increase, although there has been some increase seen in the past in at least one trial. These are of other disease-modifying therapies that are associated with neuroprotective effects. The ability to increase MTR in lesions, in chronic lesions has not really been demonstrated in the past. There is one remyelinating therapy trial which reported seeing such changes in a post hoc analysis of a subgroup of patients who were considered responders. In general, it's been very difficult to get any evidence of remyelination or increases in myelin density in chronic T2 lesions where there's a lot of changes in the cell types that are present which seem to inhibit remyelination under normal circumstances. Does that answer your question? Great. Yeah. Yes. Thank you. Yeah. Hey, AJ, do you want to take the other two? Sure. Thanks for the question, John. In terms of how much longer we'll be tracking these patients, for the open-label extension study, we tracked them for up to five years after their initial dosing. Recall that they get annual retreatment with ATA188 and a full five years of follow-up. In terms of the dose that we're using in the phase IV study, we're now using the Cohort 4 dose. Remember, we had the two highest dose cohorts, Cohort 3 and Cohort 4, and then the Cohort 4 dose was the dose at which we saw the best EDSS improvement, and that's what's continued on into the randomized control study. Okay, great. Thank you. Thank you. Thank you. Our next question today is coming from Salim Syed from Mizuho. Your line is now live. Great. Congrats on the data, guys, and thanks for the color. I had three questions for Dr. Arnold, if that's okay. Dr. Arnold, I know you spoke about the relationship between MTR decrease and EDSS worsening. I'm wondering if there's any reason why that relationship wouldn't hold on the increased sides, MTR increase and EDSS improvement, and what's a clinically meaningful MTR increase there? The second question is on the color provided on the patients that went from, for example, from a walker to a cane or are now walking a few 100 m unassisted. Have you seen this in your particular practice before with any other drugs or anything else that can explain this if you think this drug is not working, ATA188? Just lastly, on slide 19, when we look at the clustering of patients for the change in EDSS score zero, there seems to be some variation in the change in MTR, and I'm just curious how you're interpreting that variation for the EDSS zero patients. Thank you. Thanks for those questions, if I can remember them. The question of what's a clinically meaningful increase in MTR, I think is one that I can't really answer in the sense that MTR is a biomarker. It reports on myelin density and on the biology underlying the pathology in MS. In and of itself, it's not a clinical outcome. If you want to know what's a clinically meaningful change, you have to use pretty much a clinical outcome measure. There are very rare instances where biomarkers have been accepted by regulators as surrogate outcomes, qualified surrogate outcomes in lieu of a clinical measure. This is, as I said, very rare, and it's certainly not the case for MTR. I don't think we can say that there is a clinically meaningful threshold of change in MTR. Rather, it reports on the biology underlying clinically meaningful increases in clinical outcome measures such as EDSS or timed 25-foot walk. In terms of clinical improvement on other therapies, in recent years, it's become a more popular outcome measure because some of the more highly effective therapies have been able to show improvement in some patients. In general, this is seen in relapsing remitting patients earlier in the course of MS, but it has been seen in secondary progressive patients in some cases. In particular, I think what comes to mind is the Canadian bone marrow transplant trial where people were given a much more aggressive and a much more dangerous therapy where their immune system was essentially obliterated and replaced. Those patients showed some improvement in their disability or stabilization, and they were on a rapidly downhill course before this very aggressive therapy. Interestingly, in those patients too, the patients who were stable or improved showed benefits in terms of their MTR compared to patients who didn't improve after the therapy. In terms of the question of variability in the MTR measurements, this is in fact a noisy measurement. I won't go into the technical details, but it depends on very fine-tuning of the magnet's radio frequency transmitter chain, and little changes in that and little changes in the tuning of the system for the examination can result in small changes in the MTR. That is producing a spread in these values, which is what you're referring to. I would point out that if you look on the vertical scale, that we're talking about changes on the order of a fraction of a percent, and no measurement is perfect. This is just the expected variability for this and for most other MRI measures, actually. Got it. Thanks so much. Thank you. Next question today is coming from Tessa Romero from JPMorgan. Your line is now live. Hey, guys. Good morning, and thanks for taking our question here. Two hopefully quick ones. The first one is on the MTR data. Have you shared these data so far with regulators? If so, what has their response been? Can you remind us what time points you are collecting MTR in the RCT, and whether you think this could be a supportive imaging biomarker from a regulatory perspective? My second question might be for the company, just on the interim analysis. What is the plan for data disclosure there in order to preserve the integrity of the data? Would that update be around the regulatory outcome rather than the data itself, or how should we be thinking about that update next year? Thanks so much, guys. Thank you. I think both questions are for the company. In fact, thank you, Tessa. AJ, do you want to take the first one? I will take the second one. Sure. Tessa, I think in terms of discussions with the regulators, over time, we're going to share all the information that we have with the regulators. At the right time, we'll be having the discussions, and we include a full data package. Stay tuned as we have those ongoing discussions with them. In terms of the timing that we are going to be tracking in the phase II setting. We basically have the ability to check the MTR at any one of the time points where we do MRI measures. There we're doing MRIs in the first year at baseline three, six I'm sorry, baseline six, 9-12 months. We'll be getting the MRI results for all those time points, and we'll have MTR potentially at all of those as well. The main reason for that is, as Doug mentioned, we've made sure that we're conducting this trial in a fashion where the MRIs are done in a way that we can get MTR at every single time point from every center. For your second question, Tessa, on our planned disclosure related to the IA. The IA will be done and will be made available to a very small number of people within the company, and of course, to preserve the integrity of the study, the team leading that development will not be made aware of the IA. This small group will then discuss with the regulators, with the FDA, about this data and the impact of this data, as we said, related to the potential to transform this robust phase II program that we are, the EMBOLD study, into one pivotal study. Also will then decide whether we increase the sample size. We will not communicate the IA data publicly. What we will be able to communicate at the appropriate time is our decision following the IA. As we discussed in the past, we can envisage today different type of decision. One is just to say we're continuing the study with a target enrollment of 80 patients, or we can say, following the IA, we're continuing the study, and we decided to increase slightly the enrollment by some more patients, like, say, 20 more. We can also say we've done the IA, we've discussed with the FDA, and now we're transforming this robust phase II into a phase III study, where in that case, very likely many more patients, like 100 more, whatever. That will be the type of communication we are envisaging today, which is really about the consequence of this interim analysis and the decision regarding sample size and the discussion with the FDA. Does it answer your question? Yeah, absolutely. Thanks so much for the color and sort of laying that out for us. That's helpful. Congrats on the data here, guys. Thanks, Pascal. Thank you, Tessa. Thanks. Thank you. Thank you. Our next question today is coming from Phil Nadeau from Cowen and Company. Your line is now live. Good morning. Congrats on the data, and thanks for taking our questions. A few from us also. First, on the MTR signal, maybe asking the converse of a question that was just asked. Quantitatively, what is the correlation in MTR change with disability over time in the natural history of SPMS? Does that data exist in a quantitative way? How much would you expect MTR to go down per year for your average patient? Doug, do you want to take that one? Yeah, I will. I think those data don't really exist. I think the best correlation I've seen so far is the one that you've seen here. Having said that, the data may be available somewhere but not have been analyzed in this particular way. In general, we don't see improvements in disability, and so you're looking for slowing of the progression of disability and changes in MTR, which maybe have not been analyzed with a view towards deciding this correlation. Perfect. Okay. Kind of a similar question for the company. I guess as we've been trying to put the data in perspective, we've been looking for natural history data to speak to the rate of improvement or the duration of EDSS stability in SPMS patients. In your prepared remarks, you mentioned that these data suggest a higher rate of improvement and longer duration of improvement or stability versus natural history. We're curious what you found in the natural history to support that statement. What proportion of patients would you expect EDSS to improve, and what proportion could maintain stability or improvement over 12 or 18 months in the natural history results you've seen? Yeah. No, thank you for your question, Phil. AJ, do you want to address that one? Sure. Let's start with the progression, because delaying progression is what most other studies have looked at, right? When you're looking at the delay in progression, which of course is the natural history of progressive MS, you progress. You look at a variety of different studies that have been done. We believe that range at the 24-month timeframe of confirmed progression is around the 20%-30% number. That's from a variety of trials with anti-CD20 agents and oral agents as well. When you think about disability improvement, the main things we've seen is really somewhere between a 0%-6% EDSS improvement for placebo patients for disability improvement in a multiple clinical trial. That would be kind of the best view of natural history, is placebo patients in progressive MS trials. That 0%-6% is referencing a specific MedDay program. There are other programs that really kind of flow in right around that number set. We feel pretty comfortable that disability improvement, the 0%-6% range, and confirmed disability progression between 20%-30% at that 24 months that you've now seen us get to in the open label extension. Perfect. That's very helpful. Last question is just on the baseline measure. Can you remind us how many baseline measures were taken and whether you had data on the functional status of the patients or EDSS in the months leading into the study to confirm consistency between the baseline measure and their prior status over the months before recruitment? AJ? Yeah. We have a baseline measure, and prior to that, the requirement for entry into the study was the patient had to have confirmed progressive disease that was where they were failing prior therapies. Continued progression despite prior therapies. In terms of the formal EDSS, we have the baseline measurement. Prior to that, again, from the clinician's perspective, patient continuing to progress despite existing therapies. Perfect. Thanks for taking our questions, and congrats again on the data. Thanks, Phil. Thanks, Phil. Thank you. Next question today is coming from Michael DiFiore from Evercore ISI. Your line is now live. Hi. Hey, guys. Thanks so much for taking my question, congrats on what seems like very promising data. A few from me. Number one, just want to hone back in on slide 18. It appeared that some patients who had no sustained EDSS improvement registered changes in MTR that were either equal or greater than those patients who did have sustained EDSS improvement. How should we think about this, and might there be other pathological disease mechanisms at play here that could influence MTR? Then I have two follow-ups. Doug, do you want to take that one and then maybe AJ? I think there are two reasons at least that may underline this. One is the noise in the MTR measurement, which I alluded to before. The other is that the EDSS outcome measure is a very insensitive measure. It's perfectly possible that one could have increases in MTR that were not reflected in a significant change in the ordinal scale that underlies the EDSS. Got it. No, that's helpful. May I add a quick comment to that? Sure. I think just to expand on Doug's point, to that point on the ordinal scale, if you think about the patients who maintain EDSS, right? We've talked about if you can maintain a stable EDSS, that's a transformational therapy if you can maintain it long-term. I think that's the concept that Doug was talking about, where since EDSS is a bit insensitive at certain points, you could have significant clinical improvement and not fully register that on the EDSS. There's certainly a possibility that these stable EDSS patients are showing MTR increases but not quite getting to that point of tipping over EDSS. Real clinical improvement and real clinical benefit, but still showing stable EDSS, which kind of supports that notion that stable EDSS could be transformational in this space. Got it. That's super helpful. Follow-up question is, similarly, when you think about the plasticity of the brain in SPMS versus PPMS, could the SPMS patients who may have recovered from a relapse confounded their MTR results? Doug, do you want to address that? Yeah. The short answer is probably no. There are some subtleties. The MTR measurements in the lesions are made in the baseline unenhancing T2, so the T2 volume of lesions that was not acute at baseline. Of course, new lesions that formed on treatment are not considered in this analysis, right? We're looking at what happens in the chronic lesions. Whether changes in normal appearing tissue or in the brain in general can be associated with a relapse. There is not any good evidence for this. In general, severe relapses can have widespread effects throughout the brain. The average relapse, no. My final one is if you could just give us any color or update on the work being done to identify responders to ATA188? AJ, you want to take that one? Sorry. Maybe I can ask for a clarification. Meaning in terms of identifying responders, are you asking for additional translational data or longer-term information? No. I realize. I guess, to identify responders in terms of patients who might exhibit sustained disability improvement rather than just maintain their disease, which I recognize can be considered a win also. Yeah. Yeah. I think Yeah. I think one way to look at it. Okay, go ahead, AJ. No, go, Pascal. Yeah. No, I think one aspect that is interesting that we've seen in this study is that the improvers, the EDSS improvers, could be male or female, could have had anti-CD20 or not, could be SPMS or PPMS. So far there have been a variety of responders. We have not identified a particular element that could say, "Okay, this is predictive of having an improvement in EDSS compared with just the stability in the EDSS." Of course, we're going to continue to investigate, and certainly the randomized control trial will give us further element of understanding of how this product is working in patients. Great. Thanks very much. Again, congrats on the data, guys. Thank you. Thank you. Next question today is coming from Matt Phipps from William Blair. Your line is now live. Hi. Thanks for taking my questions. For Dr. Arnold, I think you mentioned there's a sub-study that looked at remyelination. I assume you're referring to MD1003, which I believe you were the lead investigator on that study. Curious, what do you think about comparing the MTR data here versus the MD1003 study, and why do you think that MTR improvements, evidence of remyelination with MD1003 did not lead to EDSS improvement in their phase III trial significantly over placebo? Forgive me. What's MD1003? The high-dose version of biotin that the- Biotin? MS-SPI study, I think. Is that what you were referring to when you mentioned the sub-study? No. I thought you were mentioning the Canadian BMT study there, no? When you were talking about- I referred to the Canadian bone marrow. We call it bone marrow transplant study. It's immunoablation and autologous hematopoietic stem cell transplantation. I think what the question relates to is a post hoc analysis of a subgroup in the SYNERGY study, which showed some evidence of improved remyelination or improvement with the remyelinating therapy. There was not a similar increase in MTR associated with that improvement in that study. They looked at the chronic lesions. The study was designed to look at the chronic lesions. The study was basically not successful. This is a biotin trial of opicinumab. Relapse remitting. Well, a combination, actually, yeah. Okay. Maybe I can follow up about that. One thing, how is MTR impacted by things like inflammation and edema? How much can that impact result and how variable can that be in these patients? It's a good question. MTR can be impacted by inflammation and edema in two ways. One is just the swelling dilutes everything. It's not an MR interaction. It's just the physical reality. There are interactions with free water in acute lesions that can affect the MTR measurement. Having said that, those interactions are present in acute lesions, which have acute inflammation, which then resolves. We're not looking at those lesions in this study. We're not reporting data from those lesions. We reported here intentionally in the chronic baseline T2 lesion volume, right? Having removed from the volume all the Gd enhancing portions of T2. Not including any new acute lesions in the analysis going forward. That those issues are not relevant. Of course, they're not relevant in the normal appearing brain tissue, which doesn't have the acute inflammation. Good. Thank you. Any other questions, Matt? Good for now. Thank you. Our next question is coming from Salveen Richter from Goldman Sachs. Your line is now live. Hey, good morning. This is Elizabeth on for Salveen. Thank you for taking our questions. Just wondering if you could comment on some of the ongoing discussions that are on with partners for this program? Thank you. Oh, thank you, Elizabeth, for your question there. As you can imagine, there are many companies involved in MS or involved in autoimmune disease that are looking for true innovation treatment that potentially can be transformative for patients. There is a clear unmet medical need right now in multiple sclerosis and some other autoimmune disease about the ability to stabilize and reverse the disease there. That's particularly obvious in PMS, but not only in PMS, even in relapsing MS. We have been in contact with a large number of these companies over the last few months, and they are more and more intrigued and interested by the data we are presenting. As you know, I've been there for 2.5 years, every time we present data, we're making a step in the right direction in terms of showing something that may create a very important opportunity as a transformative therapy for MS patients. We are having these discussions. I'm not going to comment about this discussion at this stage, they are active discussions. We've been clear that moving forward, we would like to find the right partner for ATA188 to move into the pivotal studies, to be able to accelerate and expand the development program of ATA188. We'll be ready for that, we think we'll need to ally, to partner with a company having further financial and non-financial capabilities and expertise in MS. We're going to be selecting the right partner at the proper time with the right way of value assumptions there for the product. Does it answer your question? Yes. Thank you. Thank you. Next question today is coming from Ben Burnett from Stifel. Your line is now live. Hey, thank you very much, and thank you for this update. I wanted to just follow up on a line of questions around potential sources of variability for MTR. I think that you alluded to and maybe spoke to a little bit, edema and sort of water content. I guess I would just ask, what is the expected variability of water content within a patient or a normal person, either patient by patient or day to day, and how much variability would you expect from that? Doug? Hello, Doug, can you take the question? Doug, you might be on mute. Sorry. I was on mute. It's a good question. If we ignore the acute lesions, which like a pimple that you might get, are acutely inflamed and do have significant changes in water. The tissue compartments we were looking in, which is the chronic T2 lesion and the normal brain tissue, do not have much in the way of changes in water content. The normal variability of the brain, just in response to hydration/dehydration is on the order of a fraction of a percent. Maybe not so different from what we're seeing here, but those things don't explain these changes because those things are not synchronized in individuals over time. If you're dehydrated one day and not dehydrated the next day, there may be a slight change in the water content of your brain. It's a source of noise, really, right? That's why we have the statistics here that show that beyond the noise, there's a significant difference between groups, which is determined by whether they improved in their EDSS or not, right? This, I don't think can be attributed to changes in water, these random changes in water, which might have tiny effects on MTR just by virtue of their dilution of the brain cells. Understood. Yeah, just trying to dig into specifically the variability, not questioning the trend. If I could just follow up. You mentioned like a 1% change in water content just based on. No. Never 1%. Sorry, what did you? I said a fraction of 1%. A fraction of percent. Got it. Maybe 0.1% or 0.2%, something like that. Okay. In response to severe changes in hydration, right? Well, is it known what 0.1% change in water content, how that would equate to a change in this MTR signal? Well, I think it could be associated with a similar change in MTR. Just by virtue of dilution, right? If you have a 0.1% increase in water, you're going to have a 0.1% decrease in the density of myelin. Because this water is basically extracellular. These are normal physiologic changes, right? The body is quite stable, but it's not perfectly stable. There are these minor fluctuations, and that may be contributing to some of the noise in this measurement. Okay. Very helpful. Thank you very much. Thank you. Our next question today is coming from Yigal Nochomovitz from Citi. Your line is now live. Hi. Great. Thank you very much for taking the questions. I had two, one clinical and one on the ATA188 mechanism. The clinical one is maybe I can ask a previous question about responders to 188 the opposite way. For the 17 patients that didn't achieve SDI in the 12-month dose escalation, as well as the subgroup of 10 in that group that didn't achieve SDI in the OLE, was there any common feature in their baseline demographics that limited their ability to respond to ATA188? On the mechanism of 188, I'm just curious, how does an EBV-directed T-cell promote remyelination? In other words, what is the mechanism of action that explains the remyelination? Thank you. Yeah. AJ, do you want to address these two? We can chime in, Doug or myself can chime in if needed. Absolutely. I do want to frame this differently, because when we're saying response versus no response, I really have to emphasize that we believe response is both stable disease as well as improvement. Just making sure we're all on the same page. That is response to ATA188. To your point, very specifically on are there common characteristics that argue for a disability improvement versus not a disability improvement? To date, remember, this is a 24-patient study. Teasing out all of those factors is a bit early to be able to say, are there any specific factors that argue for an improvement? I think Pascal's point was very important earlier, which is that we've seen improvement across the board, across all demographic factors, whether it's age, gender, type of progressive MS, whether it's SPMS or PPMS. When you think about it from that perspective, again, trying to come up with a predictive categorization of which patients will have disability improvement, just a little bit too early with that data set. Again, very important. Response in this space for us with ATA188 is stable or improvement. From that perspective, a large majority of patients have had response in this. I think the second question you had is a good one, certainly, where what is the mechanism here? Again, when you think about the mechanism of action, what ATA188 is doing is it's eliminating the EBV- positive B cells and plasma cells, and particularly the EBV- positive B cells, that are causing that chronic inflammatory cascade. They're driving that cascade. The perspective here would be that if you're able to really, truly get into the CNS, hit areas of compartmentalized inflammation, and essentially knock those out, right? Again, antibodies, for example, can't easily do that because they can't easily access various aspects of CNS unless there's a decent breakdown in blood-brain barrier. Versus our T- cells in ATA188 has really good access. One of the thought processes is that we are actually shutting down that kind of compartmentalized inflammation, and that just allows the body's self-reparative mechanisms to then have the remyelination occur. Are there any direct effects on myelin? That would be just much more theory. I think the prevailing theory is what I mentioned to you just now. Accessing certain areas of compartmentalized inflammation that are not easily accessible by other therapies, and by shutting that down, it allows the self-repairative mechanisms to get the remyelination going. Also remember that when you're thinking about ATA188, 100% of MS patients have Epstein-Barr virus positivity. It's a very specific mechanism to attack the problem that we're seeing in these MS patients. Got it. Thank you. Thank you. We've reached the end of our question and answer session. Ladies and gentlemen, that does conclude today's teleconference and webcast. You may disconnect your lines at this time and have a wonderful day. We thank you for your participation today.