Study Update

May 26, 2020

Slides

Good day, ladies and gentlemen, and welcome to the Atara Biotherapeutics European Academy of Neurology ATA188 Data Conference Call. I would now like to turn the conference over to your host, Eric Heiligren, Vice President of Investor Relations and Finance. You may begin. Thank you, operator. Good morning, everyone, and welcome to the Atara European Academy of Neurology ATA188 data conference call. Earlier this morning, we issued a press release reporting positive data from our ongoing Phase 1a clinical trial of ATA188 presented at EAN. This press release and the slides we will be presenting during this call are available in the Investors and Media section of attarabio.com. I'm joined on the call today by Pascal Tuchamp, President and Chief Executive Officer Doctor. Jacob DuPont, Executive Vice President and Global Head of Research and Development and Doctor. Ajay Joshi, Chief Medical Officer. Also with us today is Doctor. Larry Steinman, Professor of Neurology and Neurological Sciences, Pediatrics and Genetics at Stanford University and former Chair of the Stanford University Interdepartmental Program in Immunology. To begin the call, Pascal will start off with an introduction, and then Doctor. Simon will provide an overview of the treatment needs in the progressive MS space and evolution from B cell depleting therapy to precision EBV targeted B cell therapy. A. J. Will then review the Phase 1a data that were presented at EAN and also discuss our plans for the ATA-one hundred and eighty eight program going forward. Finally, Jacob and Pascal will provide some closing remarks. I'd like to remind listeners that 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 the 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. I'll now turn the call over to Pascal. Pascal? Thank you, Eric, and thank you, everyone, for joining us today. As Eric noted, this past weekend at EAN, we presented very encouraging data from our ongoing clinical trial of ATA188, an allogeneic T cell therapy that specifically targets cells infected with Epstein Barr virus or EBV for the potential treatment of MS. As most of you know, MS is a chronic neurological autoimmune disease that affects an estimated 2,300,000 people around the world. There is a substantial unmet medical need for new transformative therapies that have the potential to stop or even reverse disease progression as well as the accumulation of permanent disability. Our goal at ATARA is to develop and bring such a therapy to MS patients. During today's call, we'll present data from our Phase 1 multicenter open label dose escalation study of ATA188 in patients with progressive forms of MS and provide some context for understanding how ATA188 fits into the landscape of currently approved and investigational MS therapies. We will also provide an overview of the 8188 development plan going forward. Joining me today is our new Head of R and D, Doctor. Jacob DuPont. Jacob joined us from Gosama Bio, where he served as the Chief Medical Officer overseeing global development, regulatory and quality activities for the company, advancing therapeutics in these areas of immunology, inflammation and oncology. He has deep and diverse expertise from cell therapy research to oncology clinical development and global regulatory approvals, and we're extremely excited to have him as Part 14 to help bring unique off the shelf allogeneic EBV T cell immunotherapies to patients in dire need. Jacob will provide an overview of our bold vision for treating progressive MS at the end of this call. First, Doctor. Larry Steinmann will go through his perspective on the treatment needs in progressive MS. I will now turn the call over to Doctor. Steinman. Hello and good morning. I just want to say good morning. I'm calling from California and I'm going to talk about the treatment needs in progressive MS and evolution from the B cell depleting therapies that we have in our armamentarium now is treating neurologists to Ataris Precision EBV targeted B cell therapy. On my computer, I'm looking at Slide number 5, which is what the unmet needs are for individuals with progressive MS. So worldwide, there are approximately 2,300,000 patients diagnosed and living with MS. Approximately 1,000,000, so roughly half of these patients have a progressive form of the disease. And with the progressive form of the disease, one expects continual clinical decline. And current treatments, though they're doing well economically and benefit patients, have only really given us in the neurology community modest results in progressive disease. I'm looking at Slide 6 and this shows 2 approved drugs, 1 an oral drug, siponimid, and its results in the clinical trial leading to its approval. Looking on the left at patients with followed for 6 months and looking at the 6 months change in disability compared to placebo. So the effective approved drug treated 1099 patients and there was a 20% progression. So disease still progressed on this disability scale and the placebo progressed 26%, enough for an approval, certainly beneficial for patients, but as you can see graphically, a modest difference at best. Primary progressive MS, the approved drug is by infusion, ocralizumab. It's an anti CD20 monoclonal antibody. I'll talk about that in a second. And in comparison with placebo, in a 24 week confirmed disability progression, the placebo group progressed 36%, ocrelizumab 30%. So current therapies delay progression. They don't fundamentally alter the course of disease. It led to a great emphasis on the role B cells just to have achieved this effect, 36% versus 30% in individuals with progressive disease. I'm now looking at Slide 7. This is looking specifically at the B cell population. So in the bone marrow, the stem cells differentiate into the early B cells, pro B cells, pre B cells. And then out of the blood circulation, we have the B cells themselves, immature, naive, more mature, and they have on their surface various forms of immunoglobulin, IgG being present in the most mature. They differentiate into a cell called the plasmoblast, which becomes a mature plasma cell and actually secretes the immunoglobulin. Immunoglobulin in the case of multiple sclerosis is doing something deleterious. During these days of the pandemic, we'd like to make IgGs for a beneficial purpose. So I wanted to give you some background on CD20. The anti CD20 therapies do not effectively target the plasma cells. As you can see from this diagram, the fully mature plasma cell that's making the deleterious IgG is not covered with the anti CD20. The anti CD20 antibodies do not effectively cross the blood brain barrier and the anti CD20s do not deplete all the circulating B cells in the circulation. In the next slide, Slide 8, I'm going to talk about the role of Epstein Barr virus in multiple sclerosis. A team of academics joined by the scientists at Atara have reviewed this in a journal called Trends in Molecular Medicine. And I want to call your attention to the diagram on the right side of the slide. So, Epstein Barr virus is from the herpes virus family and nearly all of us have been exposed to EBV. It infects our B cells. Somehow in multiple sclerosis, this EBV infection leads to the entrance of these infected B cells into the brain. Once in the brain, these cells drive the pathology of multiple sclerosis. They produce antibodies which damage the myelin sheath and the underlying neurons. This calls into attention the immune system shown to the left in the blood vessel, those green cells that look like they're activated and the T cells come in and they start destroying the infected B cells in the brain. They also come in and they start targeting these fragments of debris and this all culminates between the EBV infection and the subsequent T cell attack in damage in the nervous system to the myelin sheath and the neurons that underlie that. Going to Slide 9, there is growing evidence that Epstein Barr virus has a major role in the pathogenesis of HEPs. There's a lot of publications and some are cited on this slide showing that prior EBV infection is necessary for an individual to develop MS. And multiple sclerosis may be mediated by those actual B cells that are infected with Epstein Barr virus. In MS patients, those B cells are not effectively eliminated And this leads to growing inflammation. There's a photo micrograph in the bottom portion of the slide and this was a collaboration between Atara and my laboratory at Stanford showing just the degree of infection in actual MS brains taken from post mortem specimens showing the diffuse and prevalent attack of the immune system in these infected cells in chronic active disease that is progressive CAP and chronic progressive disease. And also you can see individuals sometimes unaffected by MS have these EBV cells, but they're dealt with efficiently apparently because the people don't have MS. Going to Slide 10. It's a graphic of what would a transformative therapy in multiple sclerosis look like. So, shown very graphically on this scale, on the y axis, axis, we have disability. On the x axis, we have time. The timescale here could be 10, 20, 30 years. The individual is beginning of the diagnosis, fully ambulatory. And as you can see, the downhill course includes needing to walk with a cane, being in a wheelchair and then being bedridden. The current treatments and this graphic, I think demonstrates equally well from the slides that were shown earlier that were associated with the approval of the drug that the current treatments delay progression over the course of decades by no more than 6 months. If we look at Slide 11, what could a transformative therapy in MS look like? And here, one would like to intercept the disease while somebody is still ambulatory and show as shown with the blue dotted line sustained reversal of disability and halting the progression of the disease. So that's the aspiration of what ATA188 is going to try to do in the next trials. I want to show you on Slide 12 and Doctor. Joshi will get much more deeply into it that the disability improvement has to be shown with a much more granular scale that ultimately becomes a composite. Recently, MedDay has been using this scale and we'll go into detail about the ATA scale to look at the as a validated endpoint, the improvement or not in trials of progressive MS. So, this is just a bookmark to tell you that what Tara is doing with the composite scale that you'll hear in great detail shortly is now coming into the mainstream in MS therapeutic trials. So finally, what were the optimal characteristics of a treatment for progressive MS? Should be well tolerated? Should halt the disability progression? It should penetrate the CNS, the central nervous system, the brain and spinal cord, so that it turns off those cells that are causing the damage. Must target specific cell population, those B cells and plasma cells, and thereby address the underlying pathobiology. So with that, I'll turn the presentation over to Doctor. Joshi, who will take you through the trial results. Thank you. Thank you, Doctor. Steinman, and good morning, everybody. I'm going to jump into Slide 15. And you've already heard from Doctor. Steinman the growing evidence of the role of Epstein Barr virus in multiple sclerosis And of all the many different factors that have been implicated in MS, EBV is the only necessary risk factor identified. And that's an important piece because this concept of the Epstein Barr virus infected B cell as being an important player in the immune cascade that is involved in propagating both the progressive and relapsing forms of MS is growing in evidence. And AT188 is specifically designed as an Epstein Barr virus targeted T cell immunotherapy to target and eliminate those Epstein Barr virus infected cells. This study is a first in human study that's being conducted in the U. S. And Australia. And it has 2 parts to it. 1 is a dose escalating portion with an open label extension. The second part is a randomized control study. We're going to be reporting today on data from the dose escalation portion from a data cut as of April 2020. Moving on to Slide 16. This is how HAE-one hundred and eighty eight is manufactured. Key points here are we start with a healthy donor and we take a donation of white blood cells from that healthy donor. And the important piece is we expose those white blood cells to the MS related Epstein Barr virus antigens. Those white blood cells and men are co cultured with those antigens and we expand those cells, so we essentially have a large population of activated EBV specific cytotoxic T cells that we then fully characterize and place them in our library of different HLA Epstein Barr virus targeted T cells. Then when a patient needs the therapy, we simply take their HLA characteristics, match one HLA. So this is a very limited HLA match that's necessary. We match 1 HLA, which is the HLA restriction through which the cell death is killing. And then we just need to match one other. So it's 2 HLAs total. The most important match is the HLA through which the T cell death is killing. Then that cell therapy is delivered to the patient within 3 days and it is administered in an IV infusion that's over 5 to 10 minutes. Moving on to Slide 17. So here's a study design for the Phase 1a portion. This was a dose escalation study with 4 cohorts. Each cohort had 6 patients in there. The dosing in the cohorts have doubled from cohort 1 from cohort to cohort, so up from cohort 1 at 5,000,000 cells all the way to 40,000,000 cells per dose at cohort 4. The cell therapy is administered in 2 cycles. Each cycle is 3 doses day 1, day 8, day 15 with a 2 week break and then day 1, day 8, day 15. So essentially, after that second cycle, no additional therapy is given and then we follow the patients for a full year in the initial portion of the study. Then there is an open label extension, which follows the patients for up to an additional 4 years with annual retreatment as part of the study design. You see the endpoints that are listed on the right hand side. And importantly, from an eligibility criteria perspective, patients were not on additional disease modifying therapy in the course of the study and they were required to wash out of any prior medications. Let's move on to Slide 18. And here we see the baseline characteristics of the patients. Generally, there is relative balance between male and female patients. Older patient population, as you might expect, with this disease state and they all had a significant duration of disease. When you take a look at the gadolin enhancing T1 lesions at baseline, this really gives you a sense that the majority of this patient population was a non active MS population with only 4 patients having any gadolinium enhancing lesions. There was a relative balance also between secondary and progressive MS and primary progressive MS in the study. On Slide 19, you see the prior medications history. And you'll notice in cohorts 12, there were there was less prior medication history and there was no history of anti CD20 therapy in those patients. And then cohorts 34, you do see more medication history and of course, you see patients with anti CD20. Now the call out there is that cohorts 12 were primarily patients from Australia and their practice patterns were a little bit different, so they didn't typically use a lot of disease modifying therapy at that time. The second point, however, is that the reason you don't see much CD20 therapy use there is because we did require a 6 month washout for anti CD20 therapy. So that's why, you see most of the rituximab and ocrelizumab patients in cohorts 34. Importantly, in both cohorts 3 in both cohorts 34, every brituximab patient received ocrelizumab. So essentially, there's only 3 patients in each of the cohorts, cohorts 34 that received anti CD20 therapy. And then, of course, you see the median EDSS score there of 6. So it's a relatively disabled population. Moving on to Slide 20. So we assess efficacy in 2 different ways. This is the this scale here that you're seeing is the scale that we use for our clinical trial decision making. It is a scale that we reported at Actharim. It's essentially a way to aggregate the data across all of the assessments that you see on the left and create an outcomes classification that really tries to take a look at decline versus stable and improvement. And the concept here is simply that patients who the natural course of history is natural course of disease, I should say, is to decline. And the intent here was to have data that comes in early so that we can make clinical decisions as the data begin to mature over time. So moving on to Slide 21. Here you see the data for that particular scale. And you'll notice from a clinical decline perspective, cohort 1 had 45 patients declining at the 6 12 month time point and cohorts 2, 34 at the higher doses have less patients declining. And then certainly, as a corollary then cohorts 2, 3 and 4 have more patients with improvement. And as you'll notice here, when patients do have clinical improvement, that improvement tends to be durable. And also based on these clinical improvement data, we were able to select Cohort 3 as the dose to move forward in our randomized control trial. Moving on Slide 22. When we showed those data initially at Eptarim, the biggest question was, well, can you give us more detail on the disability scores? And as the data have matured, we're now able to provide a lot more detail on disability. And we're going to show you the disability scores in 2 different ways. The first is we're going to focus on sustained disability improvement. Now this is a scale similar to what was used that Doctor. Simon covered in the MedDay study. So the criteria for disability improvement are exactly the same in the MedDay study. So EDSS improvement is defined as you see on the screen here. And time 25 foot walk improvement is also defined. So if a patient had either improvement on EDSS or time 25 foot walk, they were considered a disability improver. However, to make to actually get the qualification of sustained disability improvement, the patient has to have this improvement on confirmed consecutive time points. So for example, at 6 months, they need to show disability improvement at 3 months and then on the same parameter, have that disability improvement confirmed at 6 months. Similarly, for the 12 month time point, they needed to have 6 month disability improvement confirmed on the same parameter 12 months. And as you might have seen or noticed from Doctor. Steinman's slide, that 6 12 month time point is very similar to the Phase IIIII Med Day study where they use the 9 month 12 month time point for their confirmed disability. Let's go to the next slide please. So Slide 23. Here's the data on sustained disability improvement. And first thing you see here is from going from cohorts 1 through 4, the blue bars are the 6 month data and the magenta bars are the 12 month data. And you'll notice on the 6 month data, there's an increase in the number of patients who have sustained disability improvement with increasing dose. So cohorts 34 have 2 patients with sustained disability improvement each relative to the 1 in at 6 months in ports 12. Importantly, every patient who had disability improvement at 6 months maintained that disability improvement at the 12 month time point. And then you also see in Cohort 3 that we had the 2 disability approvers at 6 months that maintained at 12 months and then we had a 3rd patient become a disability improver at that 12 month time point. Of course, with Cohort 4, we don't have the 12 month data yet and we will look to report that at a future conference. Now a question that comes up here is what is driving this disability improvement? Is it EDSS or the Time 25 Foot Walk? So moving on to Slide 24, you see that it's primarily EDSS. In the prior slide, you noticed that there were 7 patients who showed disability and sustained disability improvement in this study. In Slide 24, you see that 5 of those patients were driven by EDSS. And again, you see that same increase in the percentage of patients who have disability improvement by EDSS with increasing dose. Now, we'd like to break that information down even a little bit more for you to give you much more detail on what those EDSS and sustained disability improvements look like. So moving to Slide 25, here are some additional details. So this lists all 7 patients who had sustained disability improvement and provides the details on type of MS and anti CD20 experience, etcetera. First things that jump out are that for the patients who experienced sustained dissolvial improvement, you see both SPMS and PPMS improvers. You'll also see that for anti CD20 exposure, there were 4 patients with sustained dystobular improvement who had prior anti CD20 exposure, 3 patients who did not have prior anti CD20 exposure. So that does not seem to be a factor in achieving SDI with ATA188. The next piece to look at is the sustained, is what parameter, where is it the parameter that we attained sustained disability improvement upon? So the first part on the column with EDSS, you'll see the 5 patients listed out that had EDSS improvement and you'll see the specific scores. So the improvement in EDSS range from 0.5 improvement all the way to a patient with an improvement of 2 points on their EDSS scores. So there were some fairly substantial some patients with some fairly substantial improvements on EDSS disability. Also when you look at the 2 patients that improved on the TIME 25 Foot Walk test, their improvement on TIME 25 Foot Walk at the 6 12 month time points were between the 37% 58% range. So again, fairly significant improvements on time 25 foot walk. Now when you look at these data, one would also wonder, well, did we just get improvement on these specific scales? Or was there a general positive movement across all of the disability parameters? So the next slide I'm going to show you will actually call those out in a lighter green. So in lighter green, you'll see the parameters where they didn't meet the clinically significant improvement, but they showed a trend for improvement in the right direction. And as you can see for sustained time 25 foot walk, all of those parameters showed a trend in the right direction. We've also added 9 hole PEC test. So that now completes the 3 different disabilities measures that we used in the study, EDSS, time 25 foot walk and 9 hole PEC test. And 9 hole pack test is primarily focused in on upper limb disability. And again, you see a good trending of improvement across all the parameters in the patients who were sustained disability improvers. Moving on to Slide 27 on safety. So there is a good safety profile for the ATA188 in this study. There were only 2 patients who had there was one patient who had a greater than 3 or greater treatment emergent adverse event and that was in Cohort 4. And that particular patient developed an MS flare about that time course of that MS flare was or relapse, I should say, was 1 week after treatment with -one hundred and eighty eight. However, that was also in the setting of an upper respiratory tract infection and a possible dental infection. So although the so that was adjudicated as that was adjudicated as not being a dose limiting toxicity and that patient was withdrawn from the study and replaced and that's why we still have data on 6 patients in the Cohort 4. Cohort 3, there was a single patient with a Grade 2 adverse event of muscle spasticity and that was being not related to the product. Next slide, we see the most common treatment related adverse events and that was really just 2 patients with vinorrhea. So moving on to Slide 29. So as you can see, there were no dose limiting toxicities and no fatal adverse events. I've described the detail on in the next few bullets already. And I think the last point to bring out here is that since this is a cell therapy, one often gets questions related to elevated cytokine levels and other adverse events that might have been seen with other cell therapies in the past. We did monitor cytokine levels in the study and we did not see elevations that were clinically relevant. So Slide 30, in conclusion, you can see that these data demonstrated the safety of AK-one hundred and eighty eight at the doses that we studied and provided the basis for us to move forward into our randomized control study with the Cohort 3 dose. And it would also offer the potential to add the Cohort 4 dose pending our 12 month data. So in other words, for our randomized controlled study, we do have an adaptive design that allows us to add the Cohort 4 dose depending on the data to come through. There's also a possible signal on clinical measures, including disability measures, which did appear to be improved with increasing dose. And that's also something we're going to be assessing in the randomized control study. There's one other point I would like to make here to provide some context and in reference to Doctor. Simon's point on the MedDay article. So when we look at the data that we have for sustained disability improvement, you notice in a med day study, they had a sustained disability improvement in from the placebo population of either 0% in their Phase twothree study or 9.2% in their Phase 3 study. So when you put the sustained disability improvement data that we provided earlier into context, it gives you a sense on what we might be able to look at in our randomized control study, because certainly, although small numbers, our sustained disability improvement scores here look favorable compared to that placebo population. Going to move on to Slide 33 to talk about where we go next from here. So we've talked about our open label extension study. And potentially, this study allows for annual retreatment for every patient that was in cohorts 1 through 4. And that annual retreatment will occur for 4 additional years. Now it's important to think about what we can accomplish in that study. So first of all, when we look at what we're seeing with these sustained disability improvements, it almost looks like a respondernonresponder scenario, where clearly those patients who have disability improvement would be classified as responders. Those patients who stay stable, we're not it's unclear. They could be responders and we'd need longer timeframe to see if they're responders or not. And then clearly, the declines are people who we would consider non responders. This open label extension study will allow us to explore all of those settings. So for the patients who improved, of course, we'll continue them on the Cohort 3 dose. For the patients who are stable, this allows us to do assessments for 4 more years. And at each year, we do 3 months, 6 months and 12 month assessments. So we'll be able to provide data, on a fairly consistent basis on those patients in the study. And the last piece is the people who didn't respond and had declined. So when you think about patients in Cohorts 12 who would go into open label extension study, they will now all be able to receive the higher dose in Cohort 3. And then if you think about the patients in Cohort 34 that may not have that may have declined, those are patients where we may actually be able to generate a response by using an HLA switch. This is a technique we use in our other oncology settings where if a patient doesn't respond to initial therapy, we can switch the HLA restriction of the cells we give them and many times that will now generate a response. So these are all things that we can assess in the open label extension study. We already have 6 patients that are enrolled in the open label extension and we expect more to continue enrolling and to report on those data sometime next year. Next slide is Slide 34. This is a bit more on our randomized control study. This is our randomized control study has now resumed enrollment activities. We did have a brief pause related to COVID-nineteen, but we've resumed activities in both the U. S. And Australia. The intent here is to enroll our first patient in Q2, Q3 of this year. And overall, we're looking to enroll to include about 22 sites across both regions in order to make sure we have a rapid enrollment timeframe. We expected a study like this because we do have a lot of endpoints that you see on the right. These endpoints will provide significant data. We're looking at multiple lumbar punctures and MRIs to make sure that we fully understand the data coming out of this study. So because of that, we'd expect a study like this to take about a year to enroll and then would and about a year to have the data readout. And of course, if this double blind placebo controlled study ends up generating positive data, the intent is then to move forward into and discuss with the regulatory authorities how we'd move forward into a pivotal program. Moving on to Slide 35. Now that, I should have mentioned the RCT is going to be focused primarily on a non active progressive MS population. That is the highest area of unmet need today. But as we all know, there's a large population of patients with MS, although a significant proportion of it is PMS and that is the portion that remains untreated because of the core disease biology here with the Epstein Barr virus infected B memory cell, being part of the disease propagation in relapsing and progressive MS, we certainly do intend to study -one hundred and eighty eight in the relapsing forms over time as well. And probably one other point to note here is that, that common pathology of that EV, the autoreactive EV, the infected, the memory cell seems to potentially play a role also in other chronic immune conditions and that EBV connection is almost as strong in spaces like lupus and rheumatoid arthritis and those are also areas that we would have opportunity in. So thinking about that, the question is, while these are large spaces, how do we actually work with the cell therapy in these large spaces? And this is where we get into Slide 36. And this is where the advantages of our allo platform really come through. Now what this slide is depicting is we have already left hand side of the screen, you're seeing what the process that we've used for the library in our current clinical trial, where we take that one donation that we talked about earlier when we talked about manufacturing of ATA188, that one donation results in about 2,500 doses of therapy already. Now the key thing is we've now already achieved the transfer of that process into a bioreactor process. And that's a really important switcher because by moving into the bioreactor process, that allows us to scale almost on an industrial scale. So it allows us to use biologic techniques to produce this product. So with a couple of additional modifications near term, we expect to be able to get to almost 40,000 doses from that single donation. So when you're when we get to that point, we're really looking at a biologics like cost of this model. And that's a really important piece, of course, when you're thinking about the spaces that we're trying to address with MS and potentially the other chronic conditions. Another element of that biologics like supply chain that will be important is the graph that you see on the right hand side. We talked about the different HLA lines that we would use to match the patients. In order to cover 95% of the MS population, we recently will need only about 10 of those lines based on our inventory model. So as you can see, that's a very manageable inventory line process and a very large scale production that allows us to have a biologic supply chain at a biologics cost of goods model. Then moving on to Slide 37. The entire biologics model is really supported by the dedicated state of the art T cell manufacturing capacity we have in Thousand Oaks. And that facility can make both T cell and CAR T immunotherapy and has already started commercial manufacturing validation activities that are progressing quite well. I'm going to stop there and hand over to Jacob. Thanks, A. J. I'm excited to be part of the team at Atara. I believe in the mission and the science of Atara as we seek to innovate T cell immunotherapy leveraging our novel allogeneic EBV T cell platform to develop treatments for patients suffering with severe disease, including solid and hematologic cancers as well as autoimmune disease. Today, we are sharing the data of these allogeneic EBV T cells administered to patients with progressive MS. These data are exciting. We believe that HCA-one hundred and eighty eight represents a bold vision to transform MS therapy. We seek to target EBV antigens to limit off target activity. ATA-one hundred and eighty eight is an off the shelf therapy that we deliver efficiently as A. J. Has described. As we have shown today, it has an excellent safety profile and does not require pre medication. ATA-one hundred and eighty eight is administered in the outpatient setting by a quick 5 to 10 minute infusion. And finally, ATA has the potential to help patients with the more severe forms of progressive MS. Importantly, there is evidence of sustained improvement with the therapy in the data presented at EAN that you've heard today. Of course, we have more work to do. And if we go to the next slide, we seek to elucidate the potential for ATA188, and we are making good progress. We expect to present translational data for ATA188 at ISCT this week. We also expect to present 12 month Phase 1a clinical results for Cohort 4 in the second half of this year. So that's additional data from the current study being presented today. And as A. J. Noted, we are initiating enrollment of our randomized double blind placebo controlled Phase Ib study of ATA188 in patients with progressive MS within the next quarter. I will now turn the call over to Pascal for closing. Pascal? Thank you, Jacob. As you heard today, we are truly encouraged by the Phase I safety efficacy data for AT1ATA. And I'm personally very excited to pursue our clinical development in the near term for the potential benefit of many multiple sclerosis patients. We have made tremendous progress so far this year and look ahead to upcoming key milestone for this program as presented by Jake. I will particularly highlight the progress we've made in terms of manufacturing process because moving to Bioreactor is something very unique in the field of cell therapy and truly allows significant ability to bring down cost of goods manufactured. We're also looking forward to achieving our other key milestones with our pipeline. Mainly, we continue to expect to initiate a BDA submission with the FDA with tab cel for patients with EBV plus bptLD. And we expect our collaborators at MSK to submit an IND for ATA-two thousand two hundred and seventy one for patients with advanced mesothelioma in Q2 or Q3 of this year. Despite unexpected challenges with the COVID-nineteen outbreak, we've been able to deliver on expectations and accomplish a lot for patients and for our shareholders. We look forward to presenting an update to you on our Q2 financial results call. Finally, I'd like to take this moment to offer a C and C effect to our amazing staff at Atara, who has shown resilience and commitment despite challenging circumstances. Also, sincere thanks to the patients who are participating in this Phase I trial of 8,188, their families, the investigators, the support teams at the clinical sites and everyone else involved in this study. That concludes our prepared remarks this morning. Would like now to turn the call back over to the operator, so we can go ahead and take your questions. Operator? Our first question comes from the line of Phil Nadeau from Cowen and Company. Your line is now open. Good morning. Congratulations on the progress and thanks for taking my questions. Just a few on the data. First, in terms of the measures for EDSS, time 25 Foot Walk and the others, was the baseline measure a single measure or were there repeat measures taken at multiple visits to establish the baseline? Yes. The baseline measure was a single measure. And on the EDSS, you showed the patients who improved. Were there patients who did declined specifically on EDSS at the 6 12 month time point for the different cohorts? Yes. So let me expand on my first answer to you and then respond to this one. So when we talked about the baseline was a single measure, baseline was a single measure, but when we had improvement, you saw improvements at 3 months, 6 months 12 months. So there was a consistency in that improved measure, which is really important as you know, because EDSS and TIME 25 foot walk both have general variability. So you want to have a confirmed assessment to say that there's been a real change there. In terms of the question on decline, there were 2 patients who declined on EDSS score out of the 4 cohorts And then all of the rest were either improvers or stable. And were you able to measure EBV positive B cells in these patients? And if so, was there any correlation between the patients with the decline in EBV positive B cells and those who responded to therapy? Yes, it's a good question. So the EBV positive B cells, the cells that we're talking about, they're comprised of very small percentage of the total B cell population. So the types of things that we're going to be looking for in our randomized control study, like in the CSF and the serum, we're actually going to be looking for things like almost 3, 4, 5 cells within the CSF. That does take some technology advancements that we're already pioneering now, but there's not great ways to look for those that small number of cells in some of those biological samples today. So we do not have that for this study, but we do anticipate having those for the RCT. Great. And then just one last question from In terms of the safety profile, was there any graft versus host disease of any level? None. None. Great. Thanks for taking the questions and congrats again on the progress. Thank you. Thank you. Our next question comes from the line of Salim Syed from Mizuho. Your line is now open. Hey, thanks so much for the color guys and congrats on the data. It looks really impressive. And nice to meet you or talk to you over the phone Jacob. Couple from me, a few from me. One on the Cohort 2, A. J, maybe could you talk to is there were there anything specific about the cohort 2 that we didn't see one patient respond on EDSS at the 6 month 12 month time point? Yes. I wouldn't say there's anything specific. I guess there's 2 things I would bring up there. One is, we do think there's when we look at this, we think there's probably a dose threshold effect as not necessarily the classic dose response and which is typical in cell therapies. So nothing unusual there. The question is what is that threshold? And Cohort 2 may not exactly have been there, which is why we think the Cohorts 3 and 4 dose are more interesting. The second piece is though that there were a couple of people who were close. Remember that the disability improvement, it requires a fairly significant change in either EDSS or TIME 25 Foot Walk and it has to be confirmed 2 consecutive time points. So if you just barely missed that, then you won't get the official improvement category. So I think those both of those factors came into play. Okay. And I'm just curious what your thoughts are now that you've seen the safety profile with Cohort 4 at least through 6 months and it looks relatively safe, what your thoughts are potentially going higher than a Cohort 4 dose in a future trial? Yes, it's a good question. Certainly, as part of our overall development plan, those are the types of things we'll look at both in terms of higher doses and different treatment regimens in terms of numbers of therapies and timings. But those are all part of future developments, not part of the current RCT, but definitely part of the overall plan. Okay. And just lastly for me on have you shared this data with the FDA or gotten any initial feedback from them? And what's the sort of path here for some sort of accelerated path like the timing on that for approval or development? Sure. It's a good question. So we haven't shared the data yet with FDA. The intent here is to get that cohort 4 12 month data. And at that time, we'll have the data on the entire Phase 1a dose escalation with MRI data and a variety of other things. And that entire package will be the basis of the discussions with FDA. And certainly, we'll be very opportunistic at that point in terms of exploring any kind of accelerated pathways that may be available to us. Yes. And we believe that RMA might be a very nice pathway with this type of medicine, but we need to have more data there. Okay, excellent. Thanks so much for the color guys and congrats again. Thanks. Thank you. Our next question comes from the line of John Newman from Canaccord. Your line is now open. Hey, good morning guys and congrats on some really interesting data here. Just had a couple of questions. I wonder if you could talk about whether you'll be using the same type of algorithm to explore dosing with a different HLA match perhaps in patients that are non responders? And then also just wonder if perhaps Doctor. Steinman or one of the members of the team could just talk about the difference in a change in EDSS for a patient that starts with a high baseline versus a patient that starts with a lower baseline? I think sometimes we hear that people often view EDSS changes as if it's the same magnitude, it's the same even if patients have a different baseline. Just wondered if we could get some thoughts on that. Thanks. Maybe I'll start with answering the first question, Jerome, and then A. J. Would take the second one. Yes, good question there. So the switch of the HLA restriction is something that will be specifically adapted to that situation of AT1, AT It's a different product, differently made and a very specific set of EBV antigens that are really the ones that are present in the MS situation in the latent phase of infection there. So the way we're going to organize this potential switch to nonrespondence is going to be very specific to IT188. Ajay, do you want to take the second question? Yes. I'm sorry. And was the second question for Doctor. Steinman for me? I didn't catch that. Either. And I apologize. Would you mind repeating that second question? I didn't totally catch it. Sure. So just wondering if you could talk about the difference between a change in EDSS when you're looking at a patient that starts with a higher score at baseline versus a change in EDSS when you're starting off with a patient that has a lower score at baseline. Got it. Understood. Thank you for the repeat there. So when you the way the EDSS score works is the higher you get, the greater the disability is. So when you get to the higher scores, really anything above the 5 into the 7 range or where 7 is wheelchair bound, changes there, a half point change there is actually a significant change. When you're at the lower portions of the scale, significant change, you really need a full point change to be relevant. So that's why when you when I showed the slide where we detailed out where the patient started and what the change was, you'd see where for clinical significance, for example, we had patients that started at 4.5 and they dropped by 1.5 for EDSS. And that was clinically significant for now. So does that answer the question? Small change is significant when you have the high EDSS scores. You need a little bit more of a change to be significant to lower end. Yes. Thank you. Thank you. This is Larry Simon. I just might add that we have to remember that these cardinal scales where we're having actual numbers have a basic pitfall. One has to remember, is it going from a cane to a wheelchair? What is the significance of that versus going from a wheelchair to being bedridden? Impossible to really give a number. But in terms of the elasticity of the scales, what Doctor. Joshi said is precisely correct. Thank you. Our next question comes from the line of Yigal Nochomovitz from Citigroup. Your line is now open. Hi. Thanks for taking the questions. Just one clarifying question on the baseline characteristics in Cohort 2. There were 6 patients, although in the chart that you presented on Slide 19, I'm seeing 4 patients with background therapies or prior therapies rather. Were the other 2 could you not identify what prior therapies they were on? Or were they not on anything previously? They were not on anything previously. Got it. Okay. And then the second question is more of a conceptual question. Obviously, with this study, you're looking at the sustained disability improvement with the EDSS or a time 25 foot walk. However, my understanding is that with the planned randomized study that the primary endpoint is actually IgG levels. So I just wanted to get sort of a better understanding from you as to how to think about that endpoint since you haven't collected data for IgG before and what gives you confidence that that's going to lead to a positive outcome on that biomarker? Thank you. It's a good question. The IgG, that study design was based off of the data we got from the ATA190 study, where we did see drops in serum IgG levels. So that was the initial basis because that's all we had quite frankly for the data. And now with this study, we certainly have more clinical data. And with the EDSS scores we've seen in this study and the sustained disability improvement, the difference here from ATA190, you have to remember is ATA190 data were single time point measures of improvement. Here you see a much more robust measure. So this is a bit more reliable from a clinical standpoint. So what we've allowed ourselves to do is we have an adaptive design for the randomized controlled study. When those Cohort 4, 12 month data come in, there's going to be opportunity for us then to adapt the study design, both from a and that adaptation could include the Cohort 4 dosing as well as an adjustment in the target endpoints. Got it. Thank you. Thank you. Our next question comes from the line of Matt Fisch from William Blair. Your line is now open. Thanks for taking my questions and providing some additional details on specific patient responses over time. Could I start with a question for Doctor. Steinman? I'm just curious what you think would be a convincing biomarker for this therapy in these patients. We just talked about IgG levels and the original ATA190 study did show had improvement in CSF IDG index, which seems like it could be a direct mechanism of action correlate. But other things maybe like change in brain volume or neurofilament light chain that you if you saw that along with obviously some EDSS improvements would really convince you that the drug was working in its mechanism? Well, what I would look for, I think all of the types of measurements that you discussed are worthwhile, but I'm always more interested in the coherence of the data. I don't rely on any one particular biomarker, but I'd like to see a coherent picture starting with what's happening with the primary and secondary endpoints and then going on to exploratory endpoints. So the question is well stated, but just to reiterate, it's the overall coherence of what we see in the data that these people like myself from academia to be, I'll put it in quotes, convinced. Sure. And can I ask a follow-up for you? In terms of the treatment landscape here in progressive multiple sclerosis, there have been some publications on patients improving EDSS or at least really stabilizing through bone marrow transplants, even intrathecal injection of MSCs in a recent study post a year or 2 ago. How do you kind of compare the data from that to what you see in this initial study? Obviously, those are more invasive therapies than what Atara has here. Well, I think that you have emphasized just that, that invasive therapies have to be considered on the impact on the individual receiving them. And then one has to be hesitant without head to head types of trials and that's unlikely to ever happen to generalize too much. But I think one likes to look at the outcome measure, the disability, what they put you through and the scalability. And I find the Atara approach tremendously exciting. That's why I'm here on the call. So I'm speaking personally as a testimonial, but I like my patients, patients under my care and guidance to get a therapy like this as opposed to something that's much harsher. Maybe I can just add something to what Doctor. Simon said. When you look at the bone marrow transplant data, the majority of that is in highly active relapsing improvements, but really in that relapsing setting and to what Doctor. Simon said, obviously, quite invasive. So they're not in the setting that we're talking about. Now the second piece is, we need to mention the mesenchymal cells. And I think this is really where there's 2 pieces that help here. One is that if you believe those data, it continues to underscore the importance of having a therapy that can access CNS resident cells. So that actually supports what we're trying to do. I think the challenge with mesenchymal cells and I hope they work, right, but the challenge with them is it's essentially another autologous approach where you're getting cells from a sternum biopsy and then making the mesenchymal cells and then administering them intrathecally. So and you're needing multiple doses of intrathecal administration. So the logistics there are quite challenging. So given that the allo approach as well as our cells inherent ability to access that CNS compartment make this, at least on our minds, a much more appealing opportunity. It makes sense. And then if I can one last question for the company. How are you thinking about potential ways that you could select the right patients, I guess, longer term? Like what is being built into this randomized portion since obviously, here there are a good number of patients that are doing well, but there are still plenty that are progressing or not seeing benefit. And so how are you thinking about maybe ways that you could select patients on various biomarkers at baseline? I don't think right now, we think we really need to look at the biomarkers. The reason I say that is because we're seeing improvement in SPMS, we're seeing improvement in PPMS, we're seeing improvement whether they've had prior exposure to CD20 or whether they've not had prior exposure to CD20. And we're seeing the improvement at all levels of EDSS that were in our studies. So right now, the question really more is what we talked about, I think, a little bit earlier, where it's that concept of HLA switch that may be an opportunity for those patients who don't respond early on. But at this point, there doesn't seem to be any Thank you. Our next question comes from the line of Anupam Rama from JPMorgan. Your line is now open. Hey, guys. Thanks so much for taking the question. Just thinking about the Ekrem 29 update and now the EAN cutoff here, it looks like in cohort 1 at 12 months and cohort 2 at 6 months, there's been one patient in each of these cohorts that are now being marked as clinical decline versus the prior externs update previously. Maybe you could talk about the accounting of patients in these cohorts? Thanks so much. Yes. So the main issues there were that, they're basically this is data entry at the sites that are missing data elements at the time of the Actrims cut. And we as we continue to do the clinical trial operations on study, we do source data verification. And as we got there, we're able to clarify those missing data elements and all of the data here have been fully verified. Got verified. Got it. Thanks for taking the question. Sure. Thank you. Our next question comes from the line of Ben Burnett from Stifel. Your line is now open. Great. Thank you so much. Congratulations on generating these data. I have really I guess just one question with regards to the improvement that you're seeing in the TIME 25 Foot Walk test. I guess, how should we interpret this in the backdrop of a patient who's improving on EDSS? I guess what I'm trying to understand is if a patient goes from needing to requiring assistance to walk to then not requiring assistance to walk, When they take that 25 foot walk test, are they taking the test at these various time points without assistance if they're improving? And does that in any way obfuscate or impact how you look at those data? And I'll just point out, so I guess what I'm looking at specifically with a patient in Cohort 3, we had a baseline EDSS of 5.5 and then achieved a score of 3.5. And it looks like the improvement on the walk test seems like it's getting worse or not as great over time. So any color on that would be much appreciated. Sure. I think when you're looking at these tests, they're very dependent on a variety of factors, which is why you need to have these confirmed time points. That particular patient, although to your point, that person didn't have that 20% improvement on the time 25 foot walk, you saw some pretty good numbers, 11%, 13%. And then when you look at the 9 hole PEC test, and this is speaking to what Doctor. Simon said, where you want to see a group of supportive data points to say you've got something here, right? You look at the 9 hole PEC test for that particular patient. Again, you need a 20% improvement in 9 hole PEG test. We saw 13%, 19% and 13%. So although they didn't hit that exact trigger, you saw significant improvements across all of the disability endpoints that correlated with what we saw on the EDSS. So I think that's the best way to look at it. Okay. And does that patient go from having to walk with assistance to no longer needing assistance? So you mean for the what does that EDSS score mean? Is that what you're asking? Yes. I guess so. And really I was just trying to understand. That one did not. I guess I was at 5.5 then moved to 3.5. So it just was an ability to have more autonomy there. Okay. Okay. That's very helpful. Okay. And then maybe if I could just ask one more question. So just with regards to your inventory model, does this also apply to the PTLD patients, wherein a few cell lines would be expected to cover the majority of patients and ten lines just so it gets you at 90 plus coverage? Or is that a separate scenario? It's a separate scenario because what's happening in PPLD, you need to cover a more diverse population. So we've said recently that we believe we need approximately 40, 40,79 to cover over 95% of the population. Whereas here in MS due to the specific genetic profile of this patient and the HLA profile of this patient, we believe with our model that we just need about 10 cell lines to cover 95% of the different products and of course the patients are different in terms of the HLA diversity. Okay. That makes sense. Excellent. Thanks so much. Thank you. Our next question comes from the line of Tony Butler from Roth Capital. Your line is now open. Good morning and thank you for the time. The question is around T1 lesions and I'm curious is it necessary to always look for patients who are progressing who are progressive patients, but have little to no T1 lesions. Is that important as opposed to those that have several or certainly some, let's say, and there is actually a decline. So despite the fact that we're looking at disability scores, I'm just trying to correlate as an earlier question was alluding to, if we can look at some MRI improvements. That's question 1, if I may. And then question 2 is around, of those patients that are seropositive, and this may seem silly, but I assume that you never convert any to seronegativity that still have MS. Is that true? And then the third question is, and you may have stated this and I apologize, I just didn't hear, is sustained disability as a primary endpoint sufficient for the FDA to say that this looks good because obviously EDSS alone were the primary endpoints in previous trials that also accompanied MR and I lesions as a criteria for the approval of those particular compounds? Thanks very much. Sure. So in terms of the T1 lesion question, the one of the big reasons we're focusing in on this non active group, which would require us to not have those lesions in there is to specifically focus in on this progressive component, because oftentimes what you see is if you have these active populations and people have improvement, just to tell you, the first criticism we got when we showed a patient who improved on this was, well, that patient had GAT enhancing lesions, they got better, so they were just resolving from a flare. So what you saw wasn't real. So we really needed to create a population where we could remove all doubt about the treatment effect if we do see 1. So that was the primary reason for that. It's not necessary because obviously we are going to over time study that relapsing population. So we will be looking at those groups. But for this RCT, we are going to limit it to people who don't have active disease. For your second question, people really don't, unless there's something very unusual, they really wouldn't become seronegative on the EBV piece. And then your third question was focused in on the accessibility of the SDI endpoint. And this is a question, obviously, we're going to have conversations with FDA at the end of the Phase 1a. Part of what we're looking at right now is that we certainly had a fairly large Phase 3 program that was just completed, unfortunately failed on the readout last this month. But that was a Phase 3 program that presumably had the conversations with FDA. So there's at least some comfort with that endpoint. And I think what's going to be important with any group that goes after SDI like this as an endpoint is that the majority of that change is driven by EDSS, because that's where the biggest comfort level is with authorities. So when you have data that show SDI plus driven by EDSS, I think that's the package of information that they would probably be comfortable with, but we'll certainly have those conversations at the end of the Phase 1a meeting. Thank you. Our next question comes from the line of Maury Raycroft from Jefferies. Your line is now open. Hi, everyone. Good morning and congrats on the update. I just wanted to clarify for your patients in cohorts 34, can you say exactly how many improved on EDSS and or T25FW in those cohorts? And if those patients received and failed on rituximab or ocrelizumab prior? Sure. So in cohorts 34, we had 4 patients improve on DDSS and 1 patient improved on time 25 foot walk. So there were 5 total patients that improved. Of those 5, 2 of them had SPMS, 3 had PPMS and 4 had prior anti CD20 exposure and 1 did not have prior anti CD20 exposure. And remember on the anti CD20 exposure, when you look at the total study, 3 did not have anti CD20 exposure and 4 did. Got it. That's helpful. Thank you. And then just wondering why do the progressive MS patients lose their ability to mount a cell mediated immune response to EBV? I guess is it because their immune system has been tolerized to the virus or are they on immunosuppressive therapies to prevent an acceleration of damage? And can you remind me if these patients are on any background immunosuppressive drugs? Sure. So, Doctor. Simon, would you like to answer that first part of the question? I'm just getting off mute. If you could just repeat the question and I'll give you a precise answer. Sure. Just wondering why the patients lose their immune response to EBV? Is it because they become tolerized to EBV to the virus? Or are they on immunosuppressive therapies that prevent the immune system from having a response? Right. In general, the immune system is going to look at those infected cells as self. The idea is to drive them using ATA188 so that they're attacked and rejected. And MS patients have an overriding tendency not to be able to reject those cells, especially upon surveillance in the CNS compartment in the brain and spinal cord. Your question is good. That's the way we're framing the answer based on data. And again, it becomes coherent with what's actually seen clinically. But it's a fundamental question that if we had all of the answers to, we'd be a lot further along in our understanding of the disease. So thank you. And I do think the other aspect is when you think about anti CD20 therapy like OCREZ or Rituxan, that's a relatively broad approach to targeting B cells in general. But with ATA188, there's a much more specific strike at the B cells that are infected with EBV that we think are positive here in MS. And maybe I'll just add one piece and then answer your second question. There are although I don't think anyone fully understands to Doctor. Simon's point, the nature of the loss of this reactivity to EBV. It is pretty well established that the longer you have MS, the more exhausted your T cells that identify EBV become. So there's definitely a pathology there, but the nature of it is still uncertain. In terms of your question on the study itself, you mentioned you asked about additional immunosuppressive therapy. All patients were required to wash out of their immunosuppressive therapy. So there were no other disease modifying therapies onboard during the course of the 12 months here. Okay. And that includes steroids too? Includes steroids. The only patient who received steroids was the patient who had that MS relapse, and that person was not part of the study anymore. Got it. Okay. Thank you very much for taking my questions. Sure. Thank you. Yes. Thank you very much for joining the Atara Biotherapeutics European Academy of Neurology AT188 ATA Conference Call. You may now disconnect. Ladies and gentlemen, this concludes today's conference call. Thanks for participating. 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