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 Hyllengren, 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 I-A 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 atarabio.com. I'm joined on the call today by Pascal Touchon, President and Chief Executive Officer, Dr. Jakob Dupont, Executive Vice President and Global Head of Research and Development, and Dr. AJ Joshi, Chief Medical Officer. Also with us today is Dr. 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 Dr. Steinman 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. AJ will then review the phase I-A data that were presented at EAN and also discuss our plans for the ATA188 program going forward. Finally, Jakob 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 2.3 million 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 a Phase I 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 ATA188 development plan going forward. Joining me today is our new Head of R&D, Dr. Jakob Dupont. Jakob joins us from Gossamer Bio, where he served as the Chief Medical Officer overseeing global development, regulatory, and quality activities for the company, advancing therapeutics in the disease 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 of our team to help bring unique off-the-shelf allogeneic EBV T-cell immunotherapies to patients in dire need. Jakob will provide an overview of our bold vision for treating progressive MS at the end of this call. First, Dr. Larry Steinman will go for his perspective on the treatment needs in progressive MS. I will now turn the call over to Dr. 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 as treating neurologists to Atara's precision EBV-targeted B-cell therapy. On my computer, I'm looking at slide number five, which is what the unmet needs are for individuals with progressive MS. Worldwide, there are approximately 2.3 million patients diagnosed and living with MS. Approximately 1 million, so roughly half of these patients, have a progressive form of the disease. With the progressive form of the disease, one expects continual clinical decline. 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 six, and this shows two approved drugs, one an oral drug, siponimod, and its results in the clinical trial leading to its approval. Looking on the left at patients with, followed for six months and looking at the six months change in disability compared to placebo. The effective approved drug treated 1,099 patients, and there was a 20% progression. 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 ocrelizumab. It's an anti-CD20 monoclonal antibody. I'll talk about that in a second. In comparison with placebo in a 24-week confirmed disability progression, the placebo group progressed 36%, ocrelizumab 30%. Current therapies delay progression. They don't fundamentally alter the course of disease.
It led to a great emphasis on the role of B cells, just to have achieved this effect 36% versus 30% in individuals with progressive disease. I'm now looking at slide seven. This is looking specifically at the B-cell population. In the bone marrow, the stem cells differentiate into the early B cells, pro-B cells, pre-B cells. Out in 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 plasmablast, 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. 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, the anti-CD20s do not deplete all the circulating B cells in the circulation. In the next slide eight, 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." I want to call your attention to the diagram on the right side of the slide. Epstein-Barr virus is from the herpes virus family, 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, B 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 nine, there's growing evidence that Epstein-Barr virus has a major role in the pathogenesis of MS.
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. 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 postmortem specimens, showing the diffuse and prevalent attack of the immune system in these infected cells in chronic active disease that is progressive, CAP, in chronic progressive disease. 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? Shown very graphically on this scale, on the Y-axis, we have disability. On the X-axis, we have time. The time scale here could be 10, 20, 30 years. The individual is beginning of the diagnosis, fully ambulatory. 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 six months. We look at slide 11. What could a transformative therapy in MS look like?
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. 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 Dr. 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 as a validated endpoint, the improvement or not in trials of progressive MS.
This is just a bookmark to tell you that what Atara is doing with the composite scale that you'll hear in great detail shortly is now coming into the mainstream in MS therapeutic trials. Finally, what would the optimal characteristics of a treatment for progressive MS? It should be well-tolerated. It 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. It must target specific cell population, those B cells and plasma cells, and thereby address the underlying pathobiology. With that, I'll turn the presentation over to Dr. Joshi, who will take you through the trial results. Thank you.
Thank you, Dr. Steinman. Good morning, everybody. I'm going to jump into slide 15. You've already heard from Dr. Steinman the growing evidence of the role of Epstein-Barr virus in multiple sclerosis. Of all the many different factors that have been implicated in MS, EBV is the only necessary risk factor identified. 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. ATA188 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 two parts to it. One is a dose-escalating portion with an open-label extension.
The second part is a randomized controlled 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 ATA188 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 are then 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. When a patient needs the therapy, we simply take their HLA characteristics, match one HLA.
This is a very limited HLA match that's necessary. We match one HLA, which is the HLA restriction through which the cell does its killing, and then we just need to match one other. It's two HLAs total. The most important match is the HLA through which the T cell does its killing. Tab- cel therapy is delivered to the patient within three days, and it is administered in an IV infusion that's over five to 10 minutes. Moving on to slide 17. Here's the study design for the phase I-A portion. This was a dose escalation study with four cohorts. Each cohort had six patients in there. The dosing of the cohorts doubled from cohort to cohort, up from cohort 1 at five million cells all the way to 40 million cells per dose at cohort four.
The cell therapy is administered in two cycles. Each cycle is three doses, day one, day eight to day 15, with a two-week break, day one, day eight, day 15. 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. There's an open-label extension, which follows the patients for up to an additional four 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. Here we see the baseline characteristics of the patients.
Generally, there's a 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 gadolinium-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 four patients having any gadolinium-enhancing lesions. There was a relative balance also between secondary progressive MS and primary progressive MS in the study. On slide 19, you see the prior medications history. You'll notice in cohorts 1 and 2, there was less prior medication history, and there was no history of anti-CD20 therapy in those patients. In cohorts 3 and 4, you do see more medication history and, of course, you see patients with anti-CD20.
The callout there is that cohorts 1 and 2 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 six month washout for anti-CD20 therapy. That's why you see most of the rituximab and ocrelizumab patients in cohorts 3 and 4. Importantly, in both cohorts 3 and 4, every rituximab patient received ocrelizumab. Essentially, there's only three patients in each of the cohorts 3 and 4, that received anti-CD20 therapy. Then, of course, you see the median EDSS score there of six, so it's a relatively disabled population. Moving on to slide 20. We assessed efficacy in two different ways.
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 ECTRIMS. 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. The concept here is simply that patients who the natural course of the disease, I should say, is to decline. 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. Moving on to slide 21.
Here you see the data for that particular scale. You'll notice from a clinical decline perspective, cohort 1 had four and five patients declining at the six and 12-month time point. In cohorts 2, 3, and 4 at the higher doses have less patients declining. Certainly, as a corollary, cohorts 2, 3, and 4 have more patients with improvement. As you'll notice here, when patients do have clinical improvement, that improvement tends to be durable. 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 to slide 22. When we showed those data initially at ECTRIMS, the biggest question was, well, can you give us more detail on the disability scores?
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 two different ways. The first is we're going to focus on Sustained Disability Improvement. This is a scale similar to what was used that Dr. Steinman covered in the MedDay study. The criteria for disability improvement are exactly the same in the MedDay study. EDSS improvement is defined as you see on the screen here. Timed 25-Foot Walk improvement is also defined. If a patient had either improvement on EDSS or Timed 25-Foot Walk, they were considered a disability improver. However, to actually get the qualification of Sustained Disability Improvement, the patient had to have this improvement on confirmed consecutive time points.
For example, at six months, they needed to show disability improvement at three months, and then on the same parameter, have that disability improvement confirmed at six months. Similarly, for the 12-month time point, they needed to have six months disability improvement confirmed on the same parameter at 12 months. As you might have seen, notice from Dr. Steinman's slide, that six and 12-month time point is very similar to the phase II/III MedDay study, where they used a nine-month and 12-month time point for their confirmed disability. Let's go to the next slide, please. Slide 23. Here's the data on sustained disability improvement. The first thing you see here is from going from cohorts one through four, the blue bars are the six-month data, and the magenta bars are the 12-month data.
You'll notice on the six-month data, there's an increase in the number of patients who have sustained disability improvement with increasing dose. Cohorts 3 and 4 have two patients with sustained disability improvement each, relative to the one at six months in cohorts 1 and 2. Importantly, every patient who had disability improvement at six months maintained that disability improvement at the 12-month time point. You also see in cohort 3 that we had the two disability improvers at six months that maintained at 12 months, then we had a third 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, we will look to report that at a future conference. A question that comes up here is: What is driving this disability improvement?
Is it the EDSS or the timed 25-foot walk? Moving on to slide 24, you see that it's primarily EDSS. In the prior slide, you noted that there were seven patients who showed sustained disability improvement in this study. In slide 24, you see that five of those patients were driven by EDSS. Again, you see that same increase in the percentage of patients who have disability improvement by EDSS with increasing dose. 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 improvers look like. Moving to slide 25, here are some additional details. This lists all seven patients who had sustained disability improvement and provides the details on type of MS and anti-CD20 experience, et cetera.
First things that jump out are that for the patients who experience sustained disability improvement, you see both SPMS and PPMS improvers. You'll also see that for anti-CD20 exposure, there were four patients with sustained disability improvement who had prior anti-CD20 exposure, three patients who did not have prior anti-CD20 exposure. That does not seem to be a factor in achieving SDI with ATA188. The next piece to look at is what parameter that we attained sustained disability improvement upon. The first bar on the column with EDSS, you'll see the five patients listed out that had EDSS improvement, and you'll see the specific scores. The improvement in EDSS range from 0.5 improvement all the way to a patient with an improvement of two points on their EDSS score. There were some patients with some fairly substantial improvements on EDSS disability.
When you look at the two patients that improved on the Timed 25-Foot Walk Test, their improvement on Timed 25-Foot Walk at the six and 12-month time points were between the 37%-58% range. Again, fairly significant improvements on Timed 25-Foot Walk. 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? The next slide I'm going to show you will actually call those out in a lighter green. 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. As you can see, for sustained Timed 25-Foot Walk, all of those parameters showed a trend in the right direction.
We've also added Nine-Hole Peg Test. That now completes the three different disabilities measures that we used in the study, EDSS, timed 25-foot walk and Nine-Hole Peg Test. A Nine-Hole Peg Test is primarily focused in on upper limb disability. 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. There was a good safety profile for ATA188 in this study. There was one patient who had a three or greater treatment-emergent adverse event, and that was in cohort four. That particular patient developed an MS flare. That time course of the MS flare was, or relapse, I should say, was one week after treatment with ATA188.
However, that was also in the setting of an upper respiratory tract infection and a possible dental infection. 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 six patients in the cohort 4. Cohort 3, there was a single patient with a Grade two adverse event of muscle spasticity, and that was deemed not related to the product. Next slide, we see the most common treatment-related adverse events, and that was really just two patients with rhinorrhea. Moving on to slide 29. As you can see, there were no dose-limiting toxicities and no fatal adverse events. I've described the detail in the next few bullets already.
I think the last point to bring out here is that since this is 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. Slide 30. In conclusion, you can see that these data demonstrated the safety of ATA188 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. It would also offer the potential to add the cohort 4 dose, pending our 12-month data. In other words, for our randomized control study, we do have an adaptive design that allows us to add the cohort 4 dose depending on the data that come through.
There's also a possible signal on clinical outcome measures, including disability measures, which did appear to be improved with increasing dose. 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 Dr. Steinman's points on the MedDay article. When we look at the data that we have for sustained disability improvement, you notice in a MedDay study, they had a sustained disability improvement from their placebo population of either 0% in their phase II/III study or 9.2% in their phase III study. 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.
Certainly, although small numbers, our sustained disability improvement scores here look favorable compared to that placebo population. I'm going to move on to slide 33 to talk about where we go next from here. We've talked about our open-label extension study. Essentially, this study allows for annual retreatment for every patient that was in cohorts 1 through 4, and that annual retreatment will occur for four additional years. It's important to think about what we can accomplish in that study. First of all, when we look at what we're seeing with these sustained disability improvers, it almost looks like a responder, non-responder scenario, where clearly those patients who have disability improvement would be classified as responders. Those patients who stay stable, it's unclear. They could be responders, and we'd need longer timeframe to see if they're responders or not.
Clearly, declines are people who we would consider non-responders. This open-label extension study will allow us to explore all of those settings. 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 four more years, and at each year, we do 3 month, 6 month, and 12 month assessments. We'll be able to provide data on a fairly consistent basis on those patients in the study. The last piece is the people who didn't respond and had decline. When you think about the patients in cohorts 1 and 2 who would go into the open-label extension study, they will now all be able to receive the higher dose in cohort 3.
If you think about the patients in cohort 3 and 4 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. These are all things that we can assess in the open-label extension study. We already have six patients that have 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. Our randomized control study has now resumed enrollment activities.
We did have a brief pause related to COVID-19, 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. Overall, we're looking to include about 22 sites across both regions in order to make sure we have a rapid enrollment timeframe. 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. Because of that, we'd expect a study like this to take about a year to enroll and then about a year to have the data readout.
Of course, if this double-blind placebo-controlled study ends up generating positive data, the intent is then to move forward and discuss with the regulatory authorities how we'd move forward into a pivotal program. Moving on to slide 35. 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. 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 ATA188 in the relapsing forms over time as well.
Probably one other point to note here is that that common pathology of that autoreactive EBV-infected B 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. Thinking about that, the question is, well, these are large spaces. How do we actually work with a cell therapy in these large spaces? This is where we get into slide 36, and this is where the advantages of our allo platform really come through. Now, what the slide is depicting is we have already demonstrated that each element of this platform can support a biologics-like supply chain.
On the 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. The key thing is we've now already achieved the transfer of that process into a bioreactor process, and that's a really important switch here because by moving into the bioreactor process, that allows us to scale almost on an industrial scale. It allows us to use biologic techniques to produce this product. With a couple of additional modifications near term, we expect to be able to get to almost 40,000 doses from that single donation. When we get to that point, we're really looking at a biologics-like cost of goods model.
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 immune 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 patient. In order to cover 95% of the MS population, we really will need only about 10 of those lines based on our inventory model.
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. Moving on to slide 37. That entire biologics model is really supported by the dedicated state-of-the-art T-cell manufacturing capacity we have in Thousand Oaks. That facility can make both T-cell and CAR T immunotherapies and has already started commercial manufacturing validation activities that are progressing quite well. I'm going to stop there and hand over to Jakob.
Thanks, AJ. 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 ATA188 represents a bold vision to transform MS therapy. We seek to target EBV antigens to limit off target activity. ATA188 is an off-the-shelf therapy that we deliver efficiently, as AJ has described. As we have shown today, it has an excellent safety profile and does not require pre-medication. ATA188 is administered in the outpatient setting by a quick five to 10-minute infusion.
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. 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 I-A clinical results for cohort 4 in the second half of this year. That's additional data from the current study being presented today. As AJ noted, we are initiating enrollment of a 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, Jakob. As you heard today, we are truly encouraged by the phase I safety and efficacy data for ATA188. I'm personally very excited to pursue our clinical development in the near term for the potential benefit of many multiple sclerosis patients. We've made tremendous progress so far this year and look ahead to upcoming key milestones for this program as presented by Jakob. 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 BLA submission with the FDA with that cell for patients with EBV-positive PTLD, and we expect our collaborators at MSK to submit an IND for ATA2271 for patients with advanced mesothelioma Q2 or Q3 of this year. Despite unexpected challenges with the COVID-19 outbreak, we've been able to deliver on expectations and accomplish lots for patients and for 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 sincere thanks 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 ATA188, their family, the investigators, the support teams at the clinical site, and everyone else involved in this study. That concludes our prepared remarks this morning. I would like now to turn the call back over to the operator so we can go ahead and take your questions. Operator?
As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from the line of Phil Nadeau from Cowen and Company. Your line is now open.
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, timed 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?
Yeah, the baseline measure was a single measure.
On the EDSS, you showed the patients who improved. Were there patients who declined specifically on EDSS at the 6 month and 12 month time point for the different cohorts?
Yeah. Let me expand on my first answer to you and then respond to this one. When we talked about the baseline was a single measure, but when we had improvement, you saw improvements at 3 months, 6 months, and 12 months. There was a consistency in that improved measure, which is really important as you know, because EDSS and timed 25-foot walk both have general variability. You want to have a confirmed assessment to say that there's been real change there. In terms of the question on a decline, there were two patients who declined on EDSS score out of the four cohorts, all of the rest were either improvers or stable.
Were you able to measure EBV positive B cells in these patients? If so, was there any correlation between the patients with a decline in EBV positive B cells and those who responded to therapy?
Yeah, it's a good question. The EBV positive B cells, the cells that we're talking about, comprise a very small percentage of the total B cell population. The types of things that we're going to be looking for in our randomized control study, like in the CSF, in the serum, we're actually going to be looking for things like almost three, four, five cells within the CSF. That does take some technology advancements that we're already pioneering now. There's not great ways to look for that small number of cells in some of those biological samples today. We do not have that for this study, but we do anticipate having those for the RCT.
Great. Just one last question from us. In terms of the safety profile, was there any graft versus host disease of any level?
None.
None. Great. Thanks for taking the questions. 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 call, guys, and congrats on the data. It looks really impressive. Nice to you meet or talk to you over the phone, Jakob. A couple from me, a few from me. One on cohort 2. AJ, maybe could you talk to, was there anything specific about the cohort 2 that we didn't see one patient respond on EDSS at the 6 month and 12 month time point?
Yeah. I wouldn't say there's anything specific. I guess there's two things I would bring up there. One is, we do think when we look at this, we think there's probably a dose threshold effect, as not necessarily the classic dose response, which is typical in cell therapies. Nothing unusual there. The question is, what is that threshold? Cohort 2 may not exactly have been there, which is why we think the cohort 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 timed 25 foot walk, it has to be confirmed two consecutive time points. If you just barely miss that, you won't get the official improvement category. I think both of those factors came into play.
Okay. I'm just curious what your thoughts are now that you've seen the safety profile with cohort 4 at least through six months, and it looks relatively safe, what your thoughts are potentially going higher than a cohort 4 in a dose in a future trial?
Yeah, 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 timing. Those are all part of future development. Not part of the current RCT, but definitely part of the overall plan.
Okay. Just lastly from me. Have you shared this data with the FDA yet or gotten any initial feedback from them? What's the path here for some sort of accelerated path, like the timing on that for approval?
Sure.
Or development?
Sure. It's a good question. 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 I-A dose escalation with MRI data and a variety of other things, and that entire package will be the basis of the discussions with FDA. Certainly we'll be very opportunistic at that point in terms of exploring any kind of accelerated pathways that may be available to us.
Okay, awesome.
Yeah, we believe that, for example, RMAT might be a very nice pathway with this type of medicine. We need to have more data there.
Okay, excellent. Thanks so much for the call, 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. Congrats on some really interesting data here. Just had a couple 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. Also just wonder if perhaps Dr. 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, John, and then AJ will take the second one. Yeah, good question there. The switch of the HLA restriction is something that will be specifically adapted to that situation of ATA188. 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. The way we're going to organize this potential switch in non-responders is going to be very specific to ATA188. AJ, do you want to take the second question?
Yeah, I'm sorry. Was the second question for Dr. Steinman or for me? I didn't catch that.
Either.
I apologize, would you mind repeating that second question? I know I didn't totally catch it.
Sure. 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.
Right.
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. The way the EDSS score works is the higher you get, the greater the disability is. When you get to the higher scores, really anything above the five into the seven range, or where seven 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.
That's why 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 them. 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 the lower end.
Yes. Thank you.
Thank you.
This is Larry Steinman. 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. In terms of the elasticity of the scales, what Dr. 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 question. Just one clarifying question on the baseline characteristics in cohort 2. There were six patients, although in the chart that you presented on slide 19, I'm seeing four patients with background therapies or prior therapies rather. Were the other two, 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. The second question is more of a conceptual question. Obviously, with this study, you're looking at the sustained disability improvement with EDSS or timed 25-foot walk. However, my understanding is that with the planned randomized study, that the primary endpoint is actually IgG levels. 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'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. That was the initial basis, because that's all we had, quite frankly, for the data. Now with this study, we certainly have more clinical data. 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. What we've allowed ourselves to do is we have an adaptive design for the randomized control study. When those cohort 4, 12 month data come in, there's going to be opportunity for us then to adapt the study design. 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 Phipps from William Blair. Your line is now open.
One, thanks for taking my questions and providing some additional details on specific patient responses over time. Could I start with a question for Dr. 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 one patient had improvement in CSF IgG index, which seems like it could be a direct mechanism of action correlate. Other things maybe like changes in brain volume or neurofilament light chain that 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. I'm always more interested in the coherence of the data. I don't rely on any one particular biomarker. 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. The question is well stated, but just to reiterate, it's the overall coherence of what we see in the data that the people like myself from academia to be, I'll put it in quotes, convinced.
Sure. Can I have 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 study published a year or two ago. How do you 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 invasive therapies have to be considered on the impact on the individual receiving them. One has to be hesitant without head-to-head types of trials, and that's unlikely to ever happen to generalize too much. I think one likes to look at the outcome measure, the disability, what they put you through, and the scalability. I find the Atara approach tremendously exciting. That's why I'm here on the call. I'm speaking personally as a testimonial, but I like my patients under my care and guidance to get a therapy like this as opposed to something that's much harsher.
Makes sense. Thank you.
And-
Oh, sorry. Go ahead, Joshi.
If I can just add something to what Dr. Steinman said. When you look at the bone marrow transplant data, the majority of that is in highly active relapsing disease. When you're looking at the improvements that they see there, they're great improvements, but really in that relapsing setting. To what Dr. Steinman said, obviously quite invasive. They're not in the setting that we're talking about. The second piece is when you mentioned the mesenchymal cells, and I think this is really where there's two 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. That actually supports what we're trying to do. I think the challenge with mesenchymal cells, and I hope they work, right?
The challenge with them is it's essentially another autologous approach, where you're getting cells from a sternal biopsy and then making the mesenchymal cells and then administering them intrathecally. You're needing multiple doses of intrathecal administration. The logistics there are quite challenging. Given that, the allo approach as well as our cells' inherent ability to access that CNS compartment make this, at least in our minds, a much more appealing opportunity.
That makes sense. 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, long term? 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. 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. We're seeing the improvement at all levels of EDSS that were in our study. 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. At this point, there doesn't seem to be any reason to look for subsets of patients because we've seen improvements across the variety of people that showed up in that phase I-A.
Got it. Thanks, AJ.
Thank you. Our next question comes from the line of Anupam Rama from JP Morgan. Your line is now open.
Hey, guys. Thanks so much for taking the question. Just thinking about the ACTRIMS 2019 update and now the EAN cutoff here. It looks like in cohort 1 at 12 months and cohort 2 at six months, there's been one patient in each of these cohorts that are now being marked as clinical decline versus the prior ACTRIMS update previously. Maybe you could talk about the accounting for patients in these cohorts. Thanks so much.
Yeah. The main issues there were that this was data entry. At the sites, there were missing data elements at the time of the ACTRIMS cut. As we continue to do the clinical trial operations on study, we do source data verification. As we got there, we were able to clarify those missing data elements, and all of the data here have been fully 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, and congratulations on generating these data. I have really, I guess, just one question with regards to the improvement that you're seeing in the timed 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? Does that in any way obfuscate or impact how you look at those data?
I'll just point out, I guess what I'm looking at specifically with a patient in cohort 3 who 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. 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 Timed 25-Foot Walk, you saw some pretty good numbers, 11%, 13%. When you look at the Nine-Hole Peg Test, and this is speaking to what Dr. Steinman said, where you want to see a group of supportive data points to say you've got something here, right?
You look at the Nine-Hole Peg Test for that particular patient. Again, you need a 20% improvement in Nine-Hole Peg Test. We saw 13%, 19%, and 13%. 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. I think that's the best way to look at it.
Okay. Did that patient go from having to walk with assistance to no longer needing assistance?
You mean for the, what did that EDSS score mean? Is that what you're asking?
Yeah. I guess so. I'm just trying to understand. That one did not. Okay.
This was at 5.5 and then moved to 3.5. It just was an ability.
Yep.
Have more autonomy there.
Okay. That's very helpful. Okay. Maybe if I could just ask one more question. 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 10 lines or so could get you at 90+ coverage? Is that a separate scenario?
It's a separate scenario because what's happening in PTLD, you need to cover a more diverse population. We've said recently that we believe we need approximately 40 cell line to cover over 95% of the population. Whereas here in MS, due to the specific genetic profile of this patient and HLA profile of this patient, we believe with our model that we just need about 10 cell lines to cover 95% of the population. They're 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. 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 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? 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 one, if I may.
Question two is around of those patients that are seropositive is, and this may seem silly, but I assume that you never convert any to seronegativity that still have MS. Is that true? 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? Obviously EDSS alone were the primary endpoints in previous trials that also accompanied MRI and eye lesions as a criteria for the approval of those particular compounds. Thanks very much.
Sure. In terms of the T1 lesion question, 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. 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 gadolinium-enhancing lesions. They got better, so they were just resolving from a flare. So what you saw wasn't real." We really needed to create a population where we could remove all doubt about the treatment effect if we do see one. 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. For this RCT, we are going to limit it to people who don't have active disease. For your second question, yeah, people really don't, unless there's something very unusual, they really wouldn't become seronegative on the EBV piece. Your third question was focused in on the acceptability of the SDI endpoint. This is a question, obviously, we're going to have conversations with FDA at the end of the phase I-A. Part of what we're looking at right now is that we certainly had a fairly large phase III program that was just completed, unfortunately failed on the readout this month. That was a phase III program that presumably had the conversations with FDA.
There's at least some comfort with that endpoint. 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. When you have data that show SDI plus driven by EDSS, I think that's the kind of package of information that they would probably be comfortable with. We'll certainly have those conversations at the end of the phase I-A meeting.
AJ, very helpful. Thank you.
Sure.
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 3 and 4, can you say exactly how many improved on EDSS and/or T25FW in those cohorts? If those patients received and failed on rituximab or ocrelizumab prior?
Sure. In cohorts 3 and 4, we had four patients improve on EDSS and one patient improve on Timed 25-Foot Walk. There were five total patients that improved. Of those five, two of them had SPMS, three had PPMS, and four had prior anti-CD20 exposure, and one did not have prior anti-CD20 exposure. Remember, on the anti-CD20 exposure, when you look at the total study, three did not have anti-CD20 exposure and four did.
Got it. That's helpful. Thank you. 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? Can you remind me if these patients are on any background immunosuppressive drugs?
Sure. Dr. Steinman, 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. 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. 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. Thank you.
I do think the other aspect is when you think about anti-CD20 therapy like Ocrevus or Rituxan, that's a relatively broad approach to targeting B cells in general. With ATA188, there's a much more specific strike at the B cells that are infected with EBV that we think are causative here in MS.
Maybe I'll just add one piece and then answer your second question. Although I don't think anyone fully understands, to Dr. Steinman'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. There's definitely a pathology there, but the nature of it is still uncertain. In terms of your question on the study itself, 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 on board during the course of the 12 months here.
Okay, 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. At this time, I'm showing no further questions. Ladies and gentlemen.
Thank you very much for joining.
Yes. Thank you very much for joining the Atara Biotherapeutics European Academy of Neurology ATA188 data conference call. You may now disconnect.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.