Good afternoon, everyone. Thank you for standing by and welcome to the Atara Biotherapeutics EBV and MS Day conference call. At this time, all participants are in a listen-only mode. There will be two question and answer sessions during the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. Please be advised that today's call is being recorded. I'd now like to turn the call over to Eric Hyllengren, Vice President of Investor Relations and Finance at Atara Biotherapeutics. Please go ahead, sir.
Thank you, operator. Good afternoon, everyone, and welcome to the Atara EBV and MS Day conference call. As a reminder, an accompanying slide deck will be available in the Investors and Media section at atarabio.com at the conclusion of this call. We would like to remind listeners that during the call, the company's management will be making forward-looking statements. Actual results could differ materially from those stated or implied by our forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in the company's SEC filings. These statements are made as of today's date, and the company undertakes no obligation to update these statements.
On today's call, members from the Atara executive team, along with other scientific experts, will provide an overview of EBV and MS and review Atara's future plans for ATA188. I'd now like to turn the call over to our first presenter, Dr. Pascal Touchon, President and Chief Executive Officer of Atara. Pascal?
Thank you, Eric, and thank you all for joining us this afternoon. At Atara, we have a truly bold vision to transform the treatment of multiple sclerosis with our allogeneic T-cell therapy, ATA188. MS is a debilitating disease affecting millions with high unmet need. Here at Atara, we've been working for several years on an allogeneic T-cell therapy to target EBV infection, which has now been clearly shown to be the underlying cause of MS. Our phase I data support a favorable safety profile and the potential for disability improvement in progressive MS, which is transformative. No one has shown this before. Hence, we believe ATA188 is a potential multi-billion dollar opportunity, and we plan to deliver this medicine off the shelf and at biologic-like manufacturing cost of goods.
Momentum continues to build around this potentially transformative MS program, and today we will expand upon several aspects generating excitement in ATA188. First, recent Science and Nature papers that have identified EBV as a leading cause of MS. Compelling data from our phase I and its OLE, open-label extension. We showed 20 out of 24 patients with EDSS improvement or stability and a favorable safety profile. Additionally, MTR data suggesting that remyelination may be the biological basis for the disability improvement seen thus far in patients. We will also discuss the upcoming interim analysis, which we plan to conduct in Q2 for phase II study. We believe this IA is an extremely important catalyst for the company and is to be conducted in order to optimize the likelihood of success in phase II and confirm our current development strategy.
We are very excited about the potentially transformative nature of this product, and we are pleased to be hosting this EBV and MS Day. Now I'd like to introduce today's speakers and topics. We are joined first by three key experts in the field of neurology and MS. First, Dr. Mark Freedman, Professor of Medicine, Ottawa Hospital Research Institute, will provide an overview of MS. Next, Dr. Rajiv Khanna, Professor of Neurology at QIMR, will provide the history of ATA188. Then Dr. Larry Steinman, Professor of Neurology, Stanford, will then speak about EBV as a cause of MS. Our Chief Medical Officer, Dr. Manher Joshi, will walk us through the ATA188 phase I data previously presented at ECTRIMS last year, with some updated data from the OLE.
Before we move on, we'll take a brief break to conduct a Q&A session about the first four topics covered today. We will also have an additional Q&A session at the end of the prepared remarks. After the first Q&A session is concluded, Ajay Joshi will kick off the second half of today's discussion by providing an overview of the ongoing ATA188 phase II EMBOLD study. Dr. Jakob Dupont, our Head of R&D, will then discuss our plans for ATA188 in phase III and beyond. To conclude, I will provide my overall vision for the ATA188 program and speak about our exciting upcoming catalyst. We will then have our final Q&A sessions to finish off the day, where we'll be joined by our MS expert and also Jakob, Ajay Joshi, Kristin Yarema, Chief Commercial Officer, and Utpal Koppikar, CFO.
I'll now hand it over to Dr. Mark Freedman. Mark?
Thank you very much, Pascal. I'm Mark Freedman. I'm a professor of medicine and neurology at the University of Ottawa in Ottawa, Ontario, Canada, and the director of a large multiple sclerosis clinic. I'm very pleased to give you a very brief overview of what MS is and sort of bring you up to date on our treatments.
MS is. I'm gonna cover four, about four different topics here. A little bit about the pathophysiology, which hitherto is really unknown. Review some of the therapies, and you'll see where, hopefully the true unmet needs are in the treatment of MS, particularly patients like are depicted here as a very progressive form of MS. I think, you know, contemplating an idea of the transformational therapy you heard about, ATA188. To start, there's a lot we know but also a lot we don't know about multiple sclerosis. We know it's a central nervous system-specific autoimmune disease that attacks the lining and insulation of the wires of the central nervous system. Depending on where it hits, the central nervous system can be showing different symptoms to different patients.
central nervous system consisting mostly of the optic nerves, the brain itself, as well as brain stem and spinal cord. MS can affect any part of that. Depending on where it hits, patients will experience anything from paralysis to blindness, loss of control of their bladder, numbness, tingling. Some things that we really don't have a localization for but are very debilitating to patients is the fatigue that they suffer, as well as some of the cognitive dysfunction. Like many autoimmune diseases, we don't know the cause. We know that there's probably a blend of factors. Genetics probably gives the susceptibility that when certain genes are active and they can interact with environmental triggers, which to date have been listed as a few. Exactly how that works in translating to autoimmune disease is not clear.
One of the probably highest on the list implicating factors is a virus, and in particular, probably one of the best studied would be the Epstein-Barr virus, but many other viruses have been implicated. That you've got the susceptibility sort of loading the gun with the right genes for interacting with certain environmental triggers, and we don't know necessarily the order that these occur in. When you put them together, some patients will develop this very specific central nervous system autoimmune disease. The types of MS that have been characterized over the years are depicted in sort of a diagram where one could illustrate episodes of relapse and remission. These patients get worse, they get transiently worse with neurological symptoms and then spontaneously improve. That can go on for many years.
Sometimes the relapses don't necessarily heal all the way, so the lines don't come back to the baseline. Eventually, most patients who start out with relapsing forms of MS will yield to a more progressive course of disease, where no longer relapses are necessarily apparent, but they continue to decline due to some unknown process, which is probably independent from the process that is driving the relapses, which we think is mostly based on inflammation. Progressive forms can either arise from a relapsing form, or we also have patients who never relapse but present with a progressive neurological syndrome worked up to show that they in fact have multiple sclerosis. Whereupon you can make that diagnosis following this, these patients will or could have relapses, not to the same extent as relapsing forms, but they continue to progress over time at different rates.
We think that the progressive forms of MS share quite a bit of pathophysiology and other features that would indicate that these are very similar conditions and should be treated as a single entity. The only difference being between primary progressive and secondary progressive is in primary progressive, patients start out with their progressive form and have relapses later, whereas in the secondary progressive, they go through that relapsing phase before yielding to progression. Once you're in this progressive phase, it's possible to actually completely stagnate and go nowhere. Those are called, believe it or not, progressive patients that are non-progressive. We have secondary progressive, non-progressive or primary progressive, non-progressive. The other term that we like to point out is whether these patients continue to have activity. The activity usually refers to the inflammation.
The correlate of inflammation clinically are relapses or new lesion formation on an MRI. You could have secondary progressive that is progressive and active, meaning that the patients are getting worse but they're still having relapses or MRI lesions. Similarly, you can have active forms of progressive disease, and this will come of relevance in a few moments when I start talking a little bit more about treatments. You can also see that most of the patients are starting out relapsing with a smaller percentage that are starting out progressive. Eventually, over 15-20 years, most relapsing forms will end up progressive. For them, we have very few choices in terms of of therapies. A little bit of understanding about the pathophysiology, and I really can't go diving into this too much.
Like any autoimmune disease, for some reason, the immune system decides that there's a target that is abnormal. As long as that target exists, the immune system will continue to attack it because it considers it foreign or transformed or abnormal. This is what you want the immune system to do if you have an invasion by, say, a pathogen like a virus, or if a cell transforms into cancer, you of course want to remove it from the system. The MS is a disease where the immune system has mistaken some part of the central nervous system myelin, that insulation of the central nervous system wires, as being foreign.
Exactly what part of it is not clear, but there are some sequences of these proteins that make up myelin that have some homology to Epstein-Barr virus amino acids or antigens. These are all terms that will be defined later by one of my colleagues, so I don't wanna get into that more. Once driven to attack, you can't pull it back. The inflammation that usually comes from the ongoing stimulation of B cells and T cells leads to the damage that we see early on in MS. Later in the disease, the progressive phase is thought to be mediated perhaps more by the B cells than the T cells. Early on, certainly B cells stimulate T cells to do their damage.
To get into more than that, I think is probably more difficult for us today. The immune system is initiated usually to attack from outside the brain. These cells then find their way into the brain where they find their target and then initiate the attack, which ultimately leads to the damage we see as multiple sclerosis. With that in mind, treatment has been really focused on these cells that can replicate and move into the brain and cause the damage. Way back when, before we had any specific therapies, the way of getting rid of cells you didn't want in the immune system was to use chemotherapy. Unfortunately, the early chemotherapy-type drugs were really nonspecific, and they knocked out many different cell types, not just of the immune system but other organs.
Really there was lifelong limitations as to how much you could use, and therefore, chemotherapy has fallen aside. It was considered a bit of a Hail Mary in patients who were really on that edge of the precipice and gonna fall into progressive disease. It worked very minimally, I have to say. Then that yielded to the first generation of specific products that we call the immunomodulators, which we've had almost for 30 years.
These seem to get at the mechanism that's driving the autoimmune cells but sparing the protective form of the immune system so patients didn't end up immunosuppressed with all the kinds of problems that would go with a widespread immunosuppression, open to infection and cancer and other things that would occur if you take away the ability of the immune system to protect the body. We still use these today because they have a very high safety record, although their efficacy is a bit lower than the we'll call higher efficacy therapies, which are now focused at getting rid of lymphocytes or preventing those lymphocytes from gaining access to the central nervous system.
That's where we talk about the trafficking drugs, the anti-trafficking drugs, the very potent drugs such as the natalizumab, which blocks the entry into the brain, or the S1P inhibitors, which these more or less sequester the activated lymphocytes into the peripheral lymph nodes, so these cells can't traffic into the brain. The problem with those, of course, is as soon as you stop them, those cells are not out of the body. They're just not able to gain access, and sometimes they can accumulate and cause a very bad rebound disease. It's kind of an interim measure there, but they must be maintained in order to stop the attack. Finally, we get into the last category, which I call the lymphocyte depleters.
These are more specific drugs that can actually either deplete by destroying the cells of interest, or binding them up with an antibody that the body then eliminates through normal processes such as phagocytosis in the spleen. We've got drugs that actually have been around for a long time that have been used as forms of chemotherapy, cladribine and alemtuzumab. Then a very specific group of drugs called the anti-CD20s, which really focus on B cells. All the other drugs will have some mixture effect of B cells and T cells. Why the interest in the B cells will become clear, I think, later in this talk where you understand where the reservoir sometimes of the Epstein-Barr virus may be. What do we have then for progressive disease is very limited.
There have been a couple of studies and what these graphs in front of you will show is that there is a natural progression of these patients. As you go from left to right, you are progressing. If you're on the placebo, which on the left is considered red, I think it's the red in both of these. There's a study in secondary progressive MS, and there's a study in primary progressive MS with different drug. You'll notice that both groups are getting worse. One group that is receiving the therapy, either siponimod or cladribine, is not getting worse as fast. This is a really hard sell to patients, I have to say, because they're taking a medicine that they're hoping not to get worse.
I sort of give them the analogy of it's like jumping off a cliff and grabbing a parachute. There's no question you're going down. It's just a question of how fast. It's very hard for these patients to know, and for the physicians as well, as to whether or not a particular drug is working because everybody's getting worse. The concern would be maybe we could reverse that process, 'cause they don't wanna get worse. Let's talk about the B cells. Why did these work? In the relapsing phase, it turns out that B cells have a very strong stimulus to T cells, and probably through the repeated stimulation of T cells, they're driving that relapsing phase of disease. But in the progressive phase of illness, they may be doing something else.
They seem to congregate in and around the surface of the brain, and we see that underneath that surface of the brain, there's a lot of disease that is driving what we think is more the progressive nature of the disease because it can affect things like more cognitive dysfunction, which we see as patients get more progressive. They also are the source of antibodies, and for the longest time, we've diagnosed MS by measuring antibodies in the spinal fluid, which are very specific to something we didn't really know what it was, but it turns out recent data, which you'll hear about a little bit later, has revealed that a lot of the antibody that's being formed in the central nervous system, spinal fluid that we measure may be directed actually against the Epstein-Barr virus.
Anti-CD20 drugs work on the plasma cell that makes antibody. But as soon as it starts to transform into an antibody-making cell, the anti-CD20s don't work because there's no more CD20 on the surface of those cells. That's a very sort of quick overview of why in progressive phases has very minimal effects, and maybe what we need is something that will affect the cells that are making those antibodies. What could it be if we could change progressive nature of MS? To get an idea, we've always seen in the historical follow-up of MS that time is against you. The longer you have this disease, the better the chances that you're going to be disabled. I'd have to say even in the presence of current therapies, they don't stop the overall progression.
They may delay it, but they don't stop it. That's where we are today with current treatments. You can see we've deviated that curve ever so slightly, but maybe enough if you can really get a definitive therapy into patients early on, you might be able to deflect that curve considerably higher so that progression is delayed, and you can enjoy many good years. But once you're in this progressive phase of illness, very hard to change that course, as you saw from the two studies that I showed you. Just like these two lines, there's not a lot of light between those two lines, and there weren't any curves for those two clinical trials. Really a transformative therapy would have to do something very significant to the course of progression.
Either halt it, where you can see here on the green line that progression is curtailed and patients don't get any worse, or better, maybe there's a chance that they will actually recover. Now we know that if you follow patients sort of gradually with time, very few of the non-active patients, those that do not have relapses anymore, those that don't have new MRI lesions, most of those patients are gonna continue to get worse, and very few of them will stagnate or improve. There's natural abilities to improve, and we don't quite understand all of those.
If you could stop whatever the process is which is driving the progression, there may well be some residual function that could repair the nervous system, and exactly who those people are, I wish we could tell, but it's not always very clear. You end up having to treat a lot of progressive patients in the hope that you're going to capture those that might actually benefit from a treatment, such as what we're going to talk about today. You know, in these individual patients who have jumped off the cliff and have the parachute, could we stop it? Could we stop those patients from falling to the bottom of the cliff? Is it possible to stabilize them once they've jumped? This would be a really novel therapy.
It would be a game changer for sure for these individuals. Is it possible that a targeted therapy will be good enough that it can drive that efficacy without compromising any sort of safety? This is clear from all of our treatments. This is the goal, to improve the benefit and reduce the risk. The scale of EDSS we all hate, but nevertheless is the one that's been used to measure progression. There's other things that go with the progressive phase of illness, which I alluded to early on, that are hard to pinpoint where in the nervous system these are. Fatigue and cognition or cognitive problems are the number one reasons why patients can no longer work and seek disability.
If there was some way of targeting those, we would also have, you know, an important remedy for our patients. That's a very quick 30,000-foot overview of MS, and I'll be around to take some questions later. Thank you for listening.
Thank you, Dr. Freedman. Now I'd like to hand the call over to Dr. Rajiv Khanna, who will give us the history behind ATA188. Dr. Khanna?
Good afternoon. It is indeed a pleasure to share our journey of ATA188. ATA188 is an off-the-shelf T-cell therapy which is specifically designed to target EBV-infected B cells in MS patients. Next slide. Before I go through the history of ATA188, I would like to take a few minutes to discuss timeline of EBV discovery and subsequent emergence of link between EBV and MS. In 1964, Professor Tony Epstein and his colleagues from University of Bristol discovered the EBV in Burkitt lymphoma cells, which is highly endemic in Equatorial Africa and Papua New Guinea. It is remarkable coincidence that this discovery was published in The Lancet journal in March 1964, and we are hosting EBV and MS day in March 2022, exactly 58 years after discovery of EBV.
Soon after the discovery of EBV, a definitive link was established between EBV and infectious mononucleosis in 1970, which we now know is one of the major risk factor for MS. Studies published in early 1980s proposed link between EBV and MS, which was primarily based on epidemiological data. There were many more further studies published which also supported the link between EBV and MS. In 2013, we treated the first MS patient in the world with EBV-specific T-cell therapy. I'll discuss this in more detail in next slides. More recently, studies have provided unequivocal evidence that EBV has been identified as a trigger or cause of MS. Next slide. It is now almost 10 years when we first explored the possibility of using EBV-specific T-cell therapy for MS patients.
This all started with my discussion with Professor Michael Pender from Royal Brisbane and Women's Hospital, who has been passionately arguing for a critical role of EBV in the pathogenesis of MS. To be honest, Michael and I were really concerned that treating a patient with the T-cell therapy may exacerbate the clinical symptoms. In fact, there has not been for this any literature on treating in any autoimmune disease with the T-cell therapy. To remain safe and to avoid any risk, we took a special care on how we could infuse the T-cells, especially the dosing of the T-cells. We decided that we'll initially infuse very low dose of 5 million T-cells and carefully assess the patient safety after each infusion, and then progress to increase this dose to 10 million, 15 million, and finally to 20 million.
We sought approval from Australian Therapeutic Goods Administration, which is equivalent to FDA, and after considerable discussion with the TGA leadership, we were allowed to proceed with this therapy. We recruited a patient from Professor Michael Pender's clinic who was a 42-year-old male, had prior EBV exposure. He first developed MS symptoms in 1994 and continued to progress to RRMS until 2004, and then PPMS. His EDSS score was eight, as indicated by his inability to walk or transfer himself. We had expanded autologous EBV-specific T-cells, and these T-cells were adoptively transferred in four infusion, as I mentioned earlier. That is 5 million, then 10 million, then 15 and 20. After each dose, we very rigorously monitored the patient for safety aspect. We were really pleased to see that the patient completed T-cell therapy without any side effects, not even flu-like symptoms or malaise.
Following this treatment, the patient showed a remarkable improvement in cognition, reduced fatigue, work productivity, and most importantly, the patient showed reduction in the gadolinium enhancement lesions shown in the scans on the right-hand side. In addition, the patient also showed the reduction of intrathecal IgG, shown in the graphs above these scan photographs. In addition, the patient also showed increased voluntary movement, and this clinical improvement was sustained until 12 months after the last infusion. Next slide. Taking a clue from our experience with this one patient, we conducted an open-label phase I clinical trial of autologous EBV T-cell therapy in progressive MS patients. We recruited five patients with secondary progressive disease, five with primary progressive disease, and these patients were treated with escalating dose of EBV-specific T-cells, as we had done with our first patient.
These patients were rigorously monitored for safety and various clinical responses, as shown in the slide above. These included EDSS scores, fatigue, cognition, depression, quality of life, MRI and CSF analysis of IgG production. As we had seen with our first patient, the treatment was well-tolerated with no serious adverse events. Seven patients showed improvement, with six experiencing both symptomatic and objective neurological response. These clinical responses included reduction in the fatigue, improvement of the quality of life, and reduced intrathecal IgG, which was seen in three out of six patients. These clinical responses were coincident with the strong potency of the T cell products. While the T cell product with lower potency did not show any clinical benefit. I want to specifically highlight one patient that we had earlier treated in 2013, and that patient was actually recruited again into this open-label phase I study.
His clinical response, particularly the CSF IgG, is shown in the panel B on the right-hand side. If you see those gray vertical lines, these are indications of T cell infusions initially given in 2013 and then one given in late 2017. In both times, we noticed that once the patient completed the T cell infusion, there was a dramatic reduction in CSF IgG, clearly indicating that the clinical improvement we had seen in this patient was coincident with the T cell infusion. Next slide. While we had a reasonable success with the autologous T cell therapy, there were a number of challenges which limits the use of autologous T cell therapy. These included inconsistent potency of the T cells, and for many patients, the process took too long.
The inconsistent potency was probably related to the long-term treatment of these patients with other drugs that impacts on their immune system. We decided to develop an allogeneic off-the-shelf T cell therapy manufacturing process to reduce the variability and improve potency. One of the major advantage of this approach is the scalability to treat large number of patients, and this off therapy can be offered rapidly. In this process, we take white blood cells of the patient, from the healthy donors, and these cells are then trained to recognize EBV proteins, which are expressed in virus-infected cells. These cell products undergo rigorous testing to ensure safety and strong potency. After this extensive testing, these cells are stored as a bank, as an inventory in a manufacturing facility.
These cells can be matched with the MS patient with appropriate HLA allele and rapidly shipped to the clinical facilities for infusion. There are four very important features of this T cell therapy which I will reiterate again. These T cells are not genetically modified. We have reproducible and consistent process for manufacturing of these T cells, and they can cover diverse HLA profiles, which allows us to deliver this T cell therapy to different ethnic groups residing in different parts of the world. Furthermore, this therapy is very specific and selected for each patient based on their genetic background. We believe that ATA188 is potentially a groundbreaking therapy for the treatment and underlying cause of multiple sclerosis. This is a first-in-kind off-the-shelf therapy that offers precision targeting.
These T cells, following infusion, can traffic from peripheral blood to the site of the disease, as shown in the cartoon on the slide. These T cells recognize EBV-infected B cells through appropriate HLA TCR interaction and kill these virus-infected B cells and the plasma cells. We believe this mechanism of action is the primary reason for the clinical benefit we see in MS patients. Thank you.
Thank you, Dr. Khanna. Now I'd like to hand the call over to Dr. Larry Steinman, who will present an overview of EBV and the cause of MS. Dr. Steinman.
Good afternoon, everybody. Let's go to the next slide. For a long time, there's been a lot of data associating EBV infection with the development of multiple sclerosis, but there's been no clear idea of what that association means or actually the molecular mechanisms underlying the association. Definitively demonstrating this link between EBV and MS has been historically challenging to prove until now. Recent studies have added to the strong body of evidence that strongly suggests that EBV is actually the leading cause of MS and is a required trigger for the disease. Additionally, patients with MS may have a defective immune response to EBV, which may be mediated by an underlying genetic susceptibility. Finally, there is also a strong association between EBV and the pathologic lesions of MS. That further reinforces the idea that EBV is the leading causative factor in MS.
Let's go to the next slide. Numerous studies using multiple targets and different platforms have been used to detect the presence of EBV, and they demonstrate that essentially 100% of MS patients are seropositive for EBV. This establishes that EBV is the sole risk factor necessary to develop almost all cases of MS. Here's what is known specifically. Results from a meta-analysis on the risk of developing MS in individuals who are seronegative for EBV, suggests that in studies where two independent assays were used to detect EBV, no adult MS patient was classified as EBV seronegative. Additionally, when more robust EBV detection methods are applied to samples previously shown to be EBV negative, all but one was found to be EBV seropositive.
More recently, published data bolsters the idea that when multiple EBV targets and detection methods are used, essentially all MS patients tested were found to be EBV seropositive. The numbers are staggering, 3,149 out of 3,151 patients were positive. That's 99.9%. Let's go to the next slide. This January, a landmark study published in Science strongly suggests that EBV is actually the leading cause of MS and likely contributes to its progression. As described in the last slide, proving that EBV is a required trigger for MS has remained elusive for a long time because the key study required a massive set of longitudinal epidemiologic data. Millions of samples collected across decades were needed to tease out this critical link.
The recently published Science article followed more than 10 million people using samples from the U.S. military, where blood is drawn regularly as part of routine care. In this case, these samples were collected over a 20-year period. Using these samples, the study authors were able to prove this EBV and MS connection by focusing on a large population of initially EBV negative individuals who eventually developed MS. The results in the Science paper were striking. In all but one case, MS only developed after EBV infection. That is referred to as seroconversion. The authors observed that in 34 of 35 cases, individuals that were EBV negative at baseline all seroconverted before the onset of MS. If you were not infected by EBV, you did not get MS. In the slide you're looking at in the dot plot, you never see a red dot before a blue dot.
Importantly, this pattern was not observed with another member of the herpes virus family, cytomegalovirus, so it seems specific to EBV. This means that a person's chance of developing MS prior to an EBV infection is very, very small. While the risk of MS increased 32-fold after EBV infection. For context, the risk of developing lung cancer after smoking a pack a day is around only 10- to 15-fold. Additionally, the authors also observed that serum levels of a protein called neurofilament light chain, which is a biomarker of neuronal and axonal degeneration, increased not at the time of EBV infection but only after Epstein-Barr virus seroconversion. This implies that the pathogenic processes triggered by EBV only appear after EBV infection. In other words, these mechanisms take time to develop. Let's go to the next slide. What role might EBV play in MS disease pathology?
What does such an infection—why does such an infection lead to problems in some individuals and not in others? It turns out that there may be a defect in the ability in some individuals to mount an effective immune response against EBV, and it is proposed that this decrease is more pronounced as multiple sclerosis severity increases. This inability to control EBV infection is thought to be driven by underlying genetic factors. In susceptible individuals, defective elimination of EBV-infected B cells may result in the accumulation in lymphoid-like structures and eventually in the CNS, ultimately triggering inflammation. Let's go to the next slide. The next slide was work jointly done with Monica Moreno at Atara and my laboratory in Stanford. Some labs have observed the accumulation of EBV-infected B cells in MS brain tissues, and that's demonstrated in this slide.
If EBV infection is required for the development of MS and an underlying genetic defect allows for the accumulation of EBV-infected cells in places involved in MS, like the brain, then how might EBV be triggering the inflammation underlying MS pathology? This is where the second landmark paper that came from my laboratory and the laboratory of my close associates at Stanford, published in Nature at about two weeks after the Science paper, and it illuminates a little bit about a subject called molecular mimicry and how this is involved in the pathogenesis. Let's go to the next slide. This is a picture of a katydid, and the katydid has a body, thorax, and abdomen that looks like a leaf, but it's not a leaf. Molecular mimicry is a leading theory to help explain what triggers many autoimmune diseases, including MS.
It helps explain why an immune system would turn on a person's own tissues. In basic terms, it is a case of mistaken identity, or to use a military metaphor, friendly fire against one's own troops. Let's talk about how this process can explain how a foreign threat like EBV can share or mimic certain molecular characteristics or protein sequences with a protein normally found in the body, a self-protein that triggers MS pathology. Let's move to the next slide. Adding to the EBV MS epidemiology in the Science paper, my co-authors and I recently showed in Nature magazine how EBV shares or mimics a peptide sequence of a self-protein found in the brain called GlialCAM, glial cell adhesion molecule.
The damage occurs when the immune system's B cells that have been infected by EBV produce an antibody that targets EBV, and that antibody unfortunately also recognizes GlialCAM. A cross-reactive antibody was isolated from the spinal fluid of MS patients, which strongly binds to the EBV protein known as EBNA-1, Epstein-Barr nuclear antigen one, and also binds even a little more strongly to the self-protein known as GlialCAM, and does so in the brain, leading to aberrant inflammation, demyelination, and axonal destruction in MS and also in animal models where we've done this. The scientific community has been laudatory, and this work has been covered in the press ranging from The New York Times to Scientific American, so it's getting a lot of traction. Let's go to the next slide.
In summary, there's been a strong link between EBV and MS established longitudinally. EBV infects and immortalizes B cells. In some cases, the immortalized B cells may be autoreactive. In other cases, they may also traffic into the central nervous system and contribute to the pathology. We show that EBV and a self-protein have similarities in structure that trick the immune system into attacking a self brain protein while it's attacking EBV. EBV immortalized autoreactive B cells provide co-stimulation to autoreactive T cells, and these B cells themselves differentiate into the antibody, making clonal antibody against EBV and against GlialCAM. The T cells may also arise from the breaking of tolerance. It's the plasma cells that are secreting what would have been protective antibody, but they cross-react with self.
These cells are in the central nervous system, and they are causing the damage that underlies multiple sclerosis. Thank you.
Thank you, Dr. Steinman. Now, I'd like to hand the call over to our Chief Medical Officer, Dr. Manher Joshi, who will present an overview of the ATA188 phase I data. Ajay.
Thanks, Eric. Now, as we get into the phase I data, it's important to emphasize that ATA188 selectively targets specific EBV antigens called latency antigens. With this targeting, ATA188 addresses two pathways of neuroaxonal damage. First, it's designed to eliminate immortalized EBV-infected B cells that propagate inflammatory damage both on their own and in concert with autoreactive T cells, as Dr. Freedman mentioned. Secondly, ATA188 is designed to eliminate EBV-infected plasma cells, which are responsible for the molecular mimicry-related antibody damage that Dr. Steinman just described. Let's move to the next slide, please. As a reminder, here's a schematic of our phase I study with the open label extension or OLE. On the left is the phase I portion, where we enrolled mostly non-active SPMS and PPMS patients into four ascending dose cohorts of six patients each.
The highest dose cohort received eight times the dose of the lowest. Now for background, ATA188 is dosed in cycles with three treatments per cycle, so it's day 1, day 8, and day 15. In year 1, patients receive 2 cycles overt two months and then receive no additional therapy for the rest of the year. For year two and beyond, patients enter into the open-label extension, where they receive 1 cycle every year for up to four more years. As a reminder, this treatment is given via 5- to 10-minute IV infusion. There's no required pre-medication, and there's really only two hours of vital stats monitoring afterwards. Lastly, important to note here that 18 patients of the phase I study transitioned into the open-label extension. Let's move to the next slide.
Here we have the phase I data with the headliner of 33% of patients achieving disability improvement in the highest dose cohorts based on EDSS. Now, acknowledging the sample size and that these are open label data, we do see promising signals of transformative efficacy that led to initiating our randomized placebo-controlled study called EMBOLD, which is currently enrolling to confirm and expand upon these findings. Now, specifically in this phase I study, we measured disability improvement in progressive MS patients. Now importantly, as you know, there are no approved therapies for MS based on disability improvement endpoints. When we started the study, we measured disability improvement using a composite score used by MedDay as really the only company so far having gone through a phase III clinical trial in non-active progressive MS, attempting to show disability improvement as their primary endpoint.
The composite score sets two measures, the EDSS scale and timed 25-foot walk, and it was called the Sustained Disability Improvement or SDI. Achieving SDI required a clinically meaningful improvement in either EDSS or timed 25-foot walk that was confirmed at two consecutive time points in the study. Now based on the left side of the slide is a bar chart with the results. First, you can see there's a dose-related effect, such as patients in the two high-dose cohorts were more likely to achieve disability improvement than the lower dose cohorts. Second, I want to draw your attention to the numbers in the green circle at the bottom of that chart. These numbers represent how many patients achieve sustained disability improvement based just on confirmed EDSS improvement. Now I'm going to take a step back. Let me take a minute to explain EDSS.
EDSS ranges from 1-10, with higher numbers representing worsening disability, up to death at 10. EDSS importantly is not a linear scale. A clinically meaningful difference at an EDSS of 5.5 or more is a 0.5-point change from baseline. While a meaningful difference at an EDSS of 3-5 requires a full 1-point change. There's also some variability in that scale, which is typically controlled in clinical trials by a more rigorous requirement that any change in EDSS must be confirmed at consecutive time points to be considered a true change. Now when we talk about EDSS improvement in our phase I, the key time points that we measured are 3, 6, and 12 months, while the open-label extension time points are 15 months and then every 3 months thereafter.
As examples, confirmed EDSS improvement could occur in the phase I at six months, meaning clinically meaningful improvement in EDSS at three months and confirmed at six. Or it could occur at 12 months, meaning clinically meaningful improvement in EDSS at 6 months and confirmed at 12. Or in the OLE, you could have the EDSS improvement occurring at any two consecutive time points, such as month 12 and 15. The reason why this is so important is a bit of foreshadowing into our phase II and EMBOLD study. In our discussions with FDA, we specifically asked what they consider to be a registration appropriate endpoint for disability improvement in MS, since there's really never been an approval based on that concept. They provided us written feedback indicating that they specifically want us to use confirmed EDSS improvement as a registration appropriate endpoint.
In other words, an endpoint that we could use to support a future approval. Now with all that in mind, you can see that in the two higher dose cohorts, 33% of patients achieved confirmed EDSS improvement at the 12-month time point. This is an exciting signal and would be transformational if confirmed in our randomized placebo-controlled EMBOLD study. Since these are open-label data, you also like to see other measures trend in the same direction to further strengthen the findings. That's what we saw. On the right-hand side is a chart with other scales and patient-reported outcomes we measured, where generally the lower scores are better. You can see that the patients with disability improvement trended better on all of these measures and actually reached statistically significant improvement on fatigue severity. Next slide, please.
Now let's move on to the open label extension. On the right side of the slide is a reminder that there were 24 patients enrolled in the phase I for initial 12 months, 18 of whom continued into open label extension. Importantly, 20 of the 24 patients have had either EDSS improvement or EDSS stability throughout their observation in the study. We'll show details on that shortly. On the left side of the slide, note that we've seen a favorable safety and tolerability profile to date for ATA188, with the longest observed patients receiving up to 3 annual treatments and up to 42 months of follow-up. There have been no safety events greater than grade 3, no dose limiting toxicities, no evidence of cytokine release syndrome or graft versus host disease observed.
We've also seen that EDSS improvement that I mentioned earlier, where has been durable. Six out of 7 patients that achieved confirmed EDSS improvement have sustained that improvement at all subsequent time points, with now the longest follow-up being greater than 39 months and ongoing. Next slide, please. This slide details each of the 7 patients with EDSS improvement that I'd mentioned. I'd like to give you a sense of what that improvement means in the context of reversing disease progression. You'll notice that the majority of patients started at EDSS 5.5 or above, which is pretty significant disability and impairment to ambulation. Following ATA188 treatment, we're seeing the clock turn back on their disability. For example, we have patient F who went from needing a walker to needing just a cane.
Patients G and C, going from requiring a cane to now being able to walk the distance of three football fields without assistance. Maybe I can give you a bit more detail on the largest improvement we've seen, which is patient E. This is someone with severe PPMS who on entering the study was at EDSS 5.5. Per the investigator, this individual was only able to walk a little over 100 yards without assistance, walked at times with a cane, required a stabilizing ankle foot orthotic, was despondent, miserable, and had that fatigue that Dr. Friedman described earlier. Their employment had to be reduced to part-time because of all of these factors. Now, this individual is through two and a half years of treatment in the study and is down to an EDSS of 3.
The person is working full-time, nearly finished a lottery, married, has donated their orthotic because they no longer need it, and no longer uses a cane, and actually has no impairment to walking. Quite a remarkable change. Now let's move on to the next slide, where we'll talk about a new data cut that we've done on the open label extension study. These are updated phase I open label extension data on EDSS with extended observation beyond what we showed at ECTRIMS last year, such that we now have up to 42 months of follow-up. This representation gives a view of the durability of EDSS improvement, which is in dark green, and EDSS stability, which is in light green.
Basically, we like seeing this much green on the slide since both improvement in EDSS and long-term stability in EDSS would represent a transformational profile relative to the natural course of disease. Now there are three groups of patients noted here from top to bottom. Let's start at the top. We have the group of 7 that showed confirmed EDSS improvement in the study. You can see that most of these patients had the first sign of EDSS improvement early. In addition, all but one patient sustained improvement at every subsequent time point. The improvement is durable, again, as I noted, with up to 39 months of follow-up and ongoing. Next is a group of 13 with EDSS stability.
The first four in this group actually did not enter the open label extension, while the remainder have all been in the study for at least two and a half years, with two of these patients passing the three-and-a-half year mark, all with stable EDSS. At the bottom of the slide is a group of four patients that experienced confirmed EDSS progression in the study. One patient actually had stability for over two years before confirmed progression, while the other three progressed earlier. Now, after we review these data, we often get the questions around whether we have any biomarkers to support these promising clinical findings. In other words, do we have something that can help explain the disability improvement that we're seeing here? On the next slide is an answer to that question.
We do have data that suggests ATA188, probably through ameliorating the autoimmune cascade driven by EBV, can allow remyelination to take place. Now remember that MS pathology causes demyelination, which leads to neuroaxonal damage. MTR, as you're seeing on the screen here, is an MRI biomarker considered to reflect the density of myelin in the central nervous system. It is the most widely used technique in clinical studies to evaluate myelination status. As you might expect, an increase in MTR suggests remyelination, whereas a decrease suggests demyelination. A lot of these MTR data or the correlation on myelination is based on how these MTR measures correlate well with histologic stains for myelin in brain tissue.
Now just stepping back to see what would we expect in MTR from progressive MS, it should decrease over time in progressive MS to reflect demyelination and progression of disease. MTR increase or remyelination can be seen in active MS as inflammatory lesions resolve, but this is not well recognized in non-active progressive MS. Let's move to the next slide. You can see here that we looked at MTR in normal appearing brain tissue on the left to get a broad view of what's happening in the brain. On the right, we focused on unenhancing T2 lesions, which are generally felt to be chronic demyelinated lesions with really no chance for recovery. One of the toughest places to try to demonstrate impact. We saw that ATA188 treated patients all had increased MTR in normal appearing brain tissue, suggesting remyelination.
At 12 months, those that had confirmed EDSS improvement at any time in the study had a greater increase in MTR than those without. Switching to unenhancing T2 lesions, and to our knowledge, the first time this has been seen in non-active PMS, there was a statistically significant increase in MTR in those patients who had confirmed EDSS improvement versus those without in unenhancing T2 lesions. Now, in addition, for both normal appearing brain tissue and unenhancing T2 lesions, these changes in MTR started to become evident around six months. Lastly, when you see that six-month time point, you start being able to connect to the clinical picture where the improvements in MTR parallel the time course of the clinical improvements in EDSS.
As you see that time course parallel, it really begins to strongly support this concept that the MTR data support remyelination as the biologic basis for the clinical disability improvements that we're seeing. Let's move to the next slide, please. Here we're providing information about the phase III siponimod study in SPMS. Let me start by saying in no way are we suggesting a direct comparison here. The intent is just to provide more context for the MTR findings that we're seeing in our study. First, you can see that the expected course for MTR in progressive MS is decreased, as we discussed, or demyelination, as is represented in the placebo group from the siponimod phase III study on the left. Siponimod in that study showed slowing of demyelination in normal appearing brain tissue at 12 months based on a smaller decrease in MTR compared to placebo.
For ATA188, you can see that ATA188 uniquely demonstrated potential remyelination at 12 months in normal appearing brain tissue based on a relatively large magnitude increase in MTR. Next slide, please. These phase I and clinical biomarker, MRI biomarker data have generated significant momentum in the MS community for us, based on the potential of ATA188. We see on the left Dr. Giovannoni, one of the leading experts in MS, commenting on how the MTR data increased his confidence on the strength of the EDSS data we've seen so far. To close this section, at the bottom is a quote from a patient responding to Dr. Giovannoni's comments. "This feels dangerously close to hope, and it makes me both excited and scared.
Fingers crossed that you're right in your prediction and it works." Now, we think this quote sums up the story and the responsibility for all of us here, and we aim to deliver on this hope in our phase II study, which we'll discuss after the first Q&A session. I'll now turn it back over to Eric, who'll lead us through it. Eric?
Thanks, AJ. We will now pause for the first Q&A session. As a reminder, this session is to address the topics covered so far, and we will cover questions on the phase II and other aspects in the future in the second session. Now I'll turn it over to the operator to lead us to the Q&A session, please.
At this time, we'll be conducting our first question and answer session. Our first question is from Tessa Romero with JP Morgan. Please proceed with your question.
Hey, guys. Thanks so much for doing this, and thanks for taking our question. My first question is for Dr. Freedman. Dr. Freedman, I was hoping to dig into some of your thoughts about MTR data a little bit more. Do you view the MTR data that Atara has shown in the phase I as compelling? Does it change how valid you think the EDSS improvements seen are? How likely is it that patients would be able to have an effect on their results for these measurements? For example, how they're feeling, how much energy they have, things like that. Thanks so much.
Thank you. You've asked a lot of questions there, but I'll focus in on the MTR because in fact it was our group that really showed that lesional MTR change has the pathological correlate of remyelination. An increase equals remyelination, decrease equals demyelination. They're very tough studies to do. This is not something that's routinely done in patients, but it can be done in a properly controlled clinical study such as this one. The problem with the EDSS, and there's lots of problems with it, but these scales are somewhat objective and somewhat subjective. If a patient is feeling rather motivated on a particular day, they'll do their best to walk a little bit further, and then that can change the overall number.
This is why we've always kind of looked at the EDSS change as somewhat soft compared to something that you couldn't change by motivation. That's where the MTR, I think, really convinces us that even regardless of the soft nature of maybe a patient's really being compelled to feel better and wanna walk better for you for your study, it would be very hard for them to change their MTR in the brain itself. It is kind of a more objective marker of repair, and that's what we're hoping to see with these types of therapies. Now, whether or not that is the correlate to fatigue and cognition and everything, that's much more poorly correlated. I'm not sure if you heard that.
Yeah. That was great.
Yeah.
Thanks so much for taking my call.
Okay. Thank you. Did I answer everything? You asked a lot, so is there something remaining?
No, I think you covered it. I have another question for you maybe later on, but that was helpful. Thank you.
Thank you.
Our next question is from John Newman with Canaccord. Please proceed with your question.
Hi there. Good afternoon. Thank you for holding the event. Thank you to all the participating physicians, especially. I have another question for Dr. Freedman. We're gonna put you to work today. Dr. Freedman, I think a lot of us on the investment side are used to thinking about relapsing remitting MS, and we sort of understand how those patients fare in terms of their disease progression, but we aren't used to thinking much about progressive MS. I wanted to ask a question. If you had a late stage progressive MS patient, let's say they had an EDSS of 5.5-6.5, what might the disability progression look like over the next one to three years, either on available treatments or on no treatment?
How likely would it be to actually see the disability improve in that patient, especially if that improvement is maintained over a few years? Thanks.
I think that's a great question, actually, because this is reflecting the inherent insensitivity of a scale such as the EDSS. It's well known that patients can hover at a certain EDSS level for many years and not change, while underneath it all, there's significant changes going on if you look at it from an MRI perspective or physiological perspective. Because in order to change the step in the EDSS, the patient has to lose a certain amount of mobility. It's very possible that these patients would actually sit and stabilize for years to come. Sometimes we thought it was how long you were already at that stage that would dictate how fast you would move.
In our efforts to try to do progressive trials, we were focusing on enriching the population for people who would inevitably go down, get worse over the time period of a clinical trial. Because imagine a placebo control where your placebo doesn't do anything, or your placebo doesn't get worse if you're measuring your treatment response as preventing people from getting worse, and your comparator doesn't get worse, you have nothing to compare it to. We were always trying to find ways of picking those patients out. I have to say, we failed miserably. There's really no way of knowing that a patient is going to get worse, over the course of the next few years. Otherwise, we would be able to enrich these studies and be able to work with a smaller N.
Otherwise, you know, you're bringing in a lot of progressive patients in the hope of seeing some benefit in just a few. How many of them would actually improve? Well, there's spontaneous improvement that we see in almost every study that's been done to date, whether we're dealing with relapsing patients or progressive patients because of the mixed nature of this disease, that we don't know what the kind of reparative mechanisms that operate in every one. If you just take someone at a given time point and follow them forward, some patients may improve on these scales, and exactly what is driving that is unclear. It's a small percentage, especially as you get into the upper ends of the EDSS scale. Those patients have already acquired quite a bit of disability that has put them into a position of immobility.
It's unlikely that they would get better. If you had a remyelinating strategy, which we've all been looking for, you'd want to grab a bunch of people who are more likely to remyelinate. I don't know who those people are, and I don't think anyone does. We don't know which ones are capable of responding in that manner. When you are launching a study like we're hoping to do with this product, you know, the frustration is that you're going to be giving it to people who may not benefit.
I think the phase I data showing that some people decline, some people just didn't do anything, is probably a good kind of a premonition as what you would see in a larger study where the people who are going to drive the response are those that are going to improve and sustain that improvement and show that they, along with that sustained improvement, they have other features such as the MTR, some change in cognition maybe, if it's possible, and/or less fatigue. There's a number of other factors that would help to substantiate what we would overall see as an improvement. I'm sorry that was a long answer, but I felt that it was important for you to understand the concept of the EDSS and its insensitivities.
Excellent. Thank you very much.
Our next question is from Salim Syed with Mizuho. Please proceed with your question.
Great. Thanks so much for the color to the panel in Atara. I guess, Dr. Freedman, you mentioned a couple of things that I would actually like to direct towards you or the panel. One related to this question that was just asked on patients that can improve in the current setting. I want to narrow it down a little bit to make it more comparable to the trial. If we're looking into the phase II trial, right? If we're looking at non-active, progressive MS patients, and you're using, like, OCREVUS or I guess MAYZENT, even though it's more active secondary progressive. Is there a percentage that you can actually give us? You can say, okay, this percentage you think is actually increasing on disability from baseline.
Put another way, I guess, what would you deem as convincing data when we get the randomized phase II trial results? Then I had a follow-up. Thank you.
Thanks. You know, with regards to either the OCREVUS or the siponimod, the MAYZENT, keep in mind that the primary endpoint was non-progression or lack of a 1-point EDSS progression, not an improvement. Neither of those studies looked at improving. But when they did sub-analysis to look and see which patients were more likely to show the effect of slowing of progression, it was in fact the active patients. Those that had recent relapses, those that had new or enhancing lesions on their MRI were more likely to be slowed in their progression with either of those two drugs. They were the same ones who also, if you did sub-analyses, looked at some improvements, but those were not the primary outcomes of those studies.
You can look for those patients who are non-active in that group, and I already alluded to the fact that they did not show that type of improvement. When you look at a non-active population as we see or we're intending to see in this phase II study, the expectation is that those patients should not improve because they're non-active. A very small percentage of them might and that's been seen. Like, I think I threw the percentage up there earlier, is about something like 6%. But you would not expect to see 20% or 30%. If they improved, it might be a transient thing, so it would be seen maybe in a few months 'cause patients are hopeful. When they go into studies, they want to get better.
They think they're getting the product, and that's the problem with the phase I study 'cause it's open label. Everybody knew they got the product. In a phase II, they'll be blinded. They'll think they're gonna get the product, but they're not gonna get the product, and we'll be able to know just what that natural history really is. If we see, you know, a number that's, you know, considerably higher than the 6%, what is it going to be meaningful, 20% or 30%, then I think we've got a game changer.
Okay. Thank you. Just a quick follow-up to that. If we see something like 20 or 30%, what percentage of your progressive MS patients do you think would end up on therapy? Would there be any populations that you would exclude? Thank you.
Well, you know, as I said to the other person who asked the question, that if there was some way of knowing which patients would respond to medicines before we gave them, we would be using them more appropriately and not, you know, pushing the patients that are unlikely to improve, so it would be futile to give those patients. I don't know how to pick out which ones are gonna benefit from those that will not. You know, everybody who's in this progressive phase has been dying for something that could possibly improve them. I would think that if the drug is approved or the treatment is approved, we'll have an EDSS range that we could use to choose patients.
As long as they're in that range, it would be unethical not to at least try it in that entire group. Unless the study generates some data at the end which says, "These are the patients that are likely to benefit, these are the patients that are unlikely to benefit." If we had that, then we could focus it in. So far, none of the studies have been able to tell us that. Only the two what I mentioned, MAYZENT and OCREVUS studies, where sub-analyses have shown that it's the active patients that are likely to benefit. Therefore, in some countries like ours, we can't even give the drug to patients who have non-active disease.
Super helpful. Thanks so much.
You're welcome.
Our next question is from Phil Nadeau with Cowen and Company. Please proceed with your question.
Hi, this is Ernie Rodriguez for Phil. Thanks again to all the panelists for an excellent presentation. My question is for Dr. Steinman. You presented very strong evidence of EBV infected B cells as a cause for MS. If we were to be able to remove all B cells and EBV-infected B cells and plasma cells, like ATA188 aims to do, what would prevent it? Would there be still memory T cells that will continue to cross-react with that antigen or like, you know, keep that process going? Is that something that could keep continue?
Well, thank you. It's a very good question. If one were able to get rid of all the B cells and plasma blasts that have been infected, there still would remain T cells that would respond. However, these memory T cells, and we actually show that in the Nature paper that there are these T cells. We studied the B cell compartment much more comprehensively, but there are the T cells. But without the B cells there to drive them, without the EBV-infected B cells, I think that the forecast that I would give is that the disease will stop in its tracks, because the primary driver is those infected cells from the B cell lineage.
I see. To reach that target, that effect, would we need to remove like 100% of the infected B cells or just a large proportion, in your opinion? Is that even something that you can measure, like let's say, pre/post-treatment on,
Well, first of all, it's a fundamental question. There isn't an answer other than making educated speculations. I think we'll have to look at dose response effects and then internally. There are studies ongoing to get the residual cells from the B compartment and the T compartment, if there are any, and study those. I would speculate, and it's only speculation, that the more comprehensive the eradication of those cells are, the better the outcome will be.
All right. Thank you very much. Just a quick one for Dr. Joshi, if I may. You discussed that, you know, patients that had improvement versus stable disease versus decline. Was there any characteristic in the baseline characteristic of those patients that differ between those three groups that you could point out?
Yeah, that's a great question. Our situation is kind of like Dr. Friedman described earlier, right? We're not seeing anything, you know, specific at this point. The good news for us is we've seen improvement across all different demographics. We've had males and females, progressive patients, secondary progressive patients, and primary progressive patients. We've had people who've had prior anti-CD20 exposure, people who are totally naive to anti-CD20s. It's really been a broad-based improvement set. At least to date, we have not seen any specific characteristics that you're asking for now.
Okay, great. Thank you. Thank you both.
That concludes our first question-and-answer session. I will now turn the call back to Eric Hyllengren.
Thank you, operator. Now we'll switch over to the second part of the call, and AJ will start by giving an overview of the phase II EMBOLD study. AJ?
Thanks, Eric. You know, we're gonna be talking a lot about how we've designed the study. I do wanna link this a little bit to the prior section. Dr. Friedman also alluded to this as well, right? That where we're in an open label setting, he mentioned that, you know, there's some, you know, variability on that EDSS scale even when you do confirmed. That's why in an open label setting, you need something like MTR to feel confident that what you're seeing is real, is kind of a real improvement, hopefully. Now, the way you control for that in your next sets of studies is really having a randomized control, a placebo randomized control. That's, as I mentioned earlier, what FDA asks us to do. Despite EDSS being imperfect, and we all acknowledge that is their preferred endpoint.
Again, the way you use that endpoint is, one, confirm it in consecutive time points. two, show it in a placebo-controlled setting. That essentially is the perfect lead into this section, which is an overview of the ATA188 phase II randomized placebo-controlled study. It is a multinational study, and as I mentioned earlier, it's called EMBOLD. We're currently enrolling 80 patients with either non-active primary progressive MS or non-active secondary progressive MS. Importantly, the criteria we're using to define these populations has been vetted by the FDA as registration appropriate criteria for these populations. Now, based on those phase I findings, we are using the highest dose cohort, which is cohort four going forward. The study randomizes patients to either ATA188 or placebo. All patients are required to have progressed despite other therapies and are on no other therapies during the study.
Primary endpoint of this phase II is confirmed EDSS improvement at 12 months, which again, as noted, has been vetted with FDA as appropriate for future registrational studies as well. Now, we'll also be assessing other measures, including patient-reported outcomes, MRI measures, and serum and CSF tests. At 12 months, we'll perform the primary analysis, and then at that point, we cross over all the patients so that everyone will be on ATA188 treatment and placebo while maintaining the blind for patients and physicians throughout that second year. After year two, patients can then transition into an open label extension study for 3 more years. Let's go to the next slide, please. Now, we already described that 33% EDSS improvement from the high dose ATA188 cohorts in the phase I study.
As we start thinking about expectations for what might happen in the EMBOLD study, we also noted that MedDay placebo data that Dr. Freedman referred to, of 0% and 6% of the phase III studies. We want to even understand that a little bit better, in terms of what we might see in the placebo population for improvement. We analyzed data from the Multiple Sclerosis Outcome Assessments Consortium database, and this is a specific database of placebo arms of multiple trials in PPMS and SPMS studies. By interrogating that database, we found that confirmed EDSS improvement based on EDSS at 6 months and confirmed at 12 months, similar to what we did in our phase IA, ranges from 4% in non-active SPMS to 5.6% in primary progressive MS.
We believe these data continue to reinforce those general estimates for expectations of EDSS improvement with respect to placebo in this non-active population that we're studying. Next slide, please. Now, this slide discusses a key important next step in the program, which is the interim analysis for the EMBOLD study that we plan to conduct in Q2 of this year. This IA is gonna inform our future development plans. Now, the key aspects of the IA are that it will be a full IA, meaning we'll do a full review of safety and efficacy data that are available at the data cutoff. The purpose is to determine whether we wanna make any sample size adjustments to maximize the probability of success for the full one-year primary analysis.
At this interim analysis, we'll have patients across various time points, including a number that have been on study for more than 12 months. That said, the key data point will be EDSS improvement at 6 months. Now, this is important because EDSS improvement at 6 months in the phase I was greater than 85% predictive of achieving confirmed EDSS improvement at 12 months. Though our IA decisions will now be made primarily on this EDSS time point, we'll also analyze other translational and biomarker data such as MTR. It should be noted that we also shared this IA plan with FDA, and they're on board with this approach. Now, as I mentioned earlier, we will make decisions on whether we will adapt the final sample size to the study based on this IA.
The current target enrollment is N = 80, and we're on track to achieve this soon after the IA is complete. In addition, the IA data will inform other aspects of our program, including the phase III design and planning, as well as continued development in phase II studies for potential new indications, which Jakob will discuss now. Jakob.
Thanks, AJ. As AJ mentioned, we're planning at this time two phase III studies, one in non-active PPMS and one in non-active SPMS. The primary endpoint is planned to be confirmed EDSS improvement at 12 months, which is aligned with our phase II EMBOLD study with the recommendations from the FDA on this topic. Importantly, we have obtained fast track designations with the agency on both patient populations and alignment with them on key study design elements. We will also consider additional phase II studies in other MS populations and in autoimmune indications after the interim analysis for EMBOLD is conducted. We're also generating retrospective and prospective real-world data at the patient level extracted from medical records of these patients with PPMS and SPMS. This will give us data on the natural history of MS disease progression in these forms of the disease.
Over this time, we will continue to have ongoing dialogue with global health authorities. If we go to the next slide. Our planned phase III study for ATA188 will use the intended commercial product, which is based on our demonstrated proof in stirred-tank bioreactors and is planned to enable biologic-like cost of goods manufactured. This scaled-up manufacturing process is planned to result in the ability to produce up to 20,000 doses from one donor collection, and we project that we will be able to cover approximately 95% of MS patients with only 10 HLA-restricted product lots. If we go to the next slide. Beyond progressive MS, there are several other autoimmune diseases that ATA188 could be studied in. We believe the mechanism of action of ATA188 can be applied across all forms of multiple sclerosis.
This belief is based on the finding that EBV-infected autoreactive B cells and plasma cells underlie all forms of MS, which leads to inflammation and disability progression. Looking beyond our current focus in progressive MS, we're evaluating studies of ATA188 across the spectrum, including early disease onset, including CIS, and in intermediate stages of relapsing disease. We believe that ATA188 could be a transformative product in these areas as well. Next slide, please. There have been numerous studies about EBV association with other autoimmune diseases, where long-standing EBV associations exist, including lupus and rheumatoid arthritis. You can see on this slide the number of publications and comments on the association of EBV with autoimmune conditions. For example, nearly half of systemic lupus erythematosus risk loci are occupied by EBV proteins and co-clustering human proteins.
Also, in addition to MS, EBV-associated proteins were found in rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, and celiac disease. We believe that ATA188 has tremendous potential for application across several autoimmune diseases. Next slide. Finally, I want to take a minute and talk about an exciting collaboration we've had for several years with the foremost experts at QIMR, including Dr. Khanna. In addition to having the most advanced EBV targeting program in ATA188, with the potential to address EBV-driven autoimmune diseases, we are also in preclinical development with a novel EBV vaccine candidate. This vaccine is a multi-subunit differentiated vaccine candidate that can provide antibody and cell-based immunity, and our preclinical data confirm the potential to stimulate both B cells and T cell responses.
We believe this vaccine has the potential to complement ATA188 in our overall portfolio, and it could be used prophylactically, therapeutically, or both. We are excited about this work as another part of Atara's leadership in addressing EBV-driven autoimmune disease. I will now turn over to Pascal, who will give us his thoughts on ATA188 now and for the future. Pascal?
Thank you, Jakob. When we take a step back and look at the broad market for MS, multiple sclerosis therapeutics, ATA188 is clearly well-positioned to potentially transform the lives of patients and change the treatment paradigm in MS through precision EBV targeting. Looking at the overall landscape for MS therapeutics over time, we have come a long way in the past 30 years, and we've learned more about the role of T and B cells in this disease. The industry developed a range of therapies to sequester, inhibit, or deplete them. Now, however, we know that EBV is the leading cause of MS from onset to progression of the disease. At the same time, Atara has in phase II development, the first-in-kind therapy precisely targeting EBV latent infection as a root cause of MS.
More specifically, we believe ATA188 has many benefits. First, it precisely targets EBV-positive B cells and plasma cells to treat MS at the source, especially as it penetrates the CNS, with the potential to improve or stabilize disability in patients. Next, the specific mechanism of action for ATA188 has been shown to limit off-target toxicity with favorable safety so far in our clinical experience. Importantly, ATA188 is expected to be an off-the-shelf, scalable, and easy to administer product for patients in need. Together, we believe these unique product attributes position ATA188 to lead the race into change the treatment paradigm in MS. Now moving on to next slide. As we heard from Dr.
Steinman earlier, the findings in Science and Nature were landmark publications and have been well received by the medical and scientific community. To this point, an independent survey of U.S. neurologists conducted prior to these recent publications showed that only one in six neurologists at that time believed that EBV was a viable therapeutic target in MS. Following the recent publication linking EBV and MS, a new survey with the same neurologists is showing this time that a large majority of them now agree that targeting EBV-infected cells is a viable therapeutic strategy for MS. This increased support from neurologists is exciting for Atara and most importantly, for patients with MS. Now on the next slide, I'd like to conclude. I think that we've covered a lot of ground on today's call.
Before we get into Q&A, I wanted to take a minute to summarize what we've discussed and what our upcoming catalysts are. At the foundation of it all, the recent landmark publication from Science and Nature confirmed the hypothesis that EBV infection causes MS. Our phase I and open-label extension data are truly compelling, with 20 out of 24 patients showing improvement or stability with EDSS. Remember, this is in a disease where unfortunately, patients are expected to only decline over time. As we've mentioned, we are on track to conduct the EMBOLD interim analysis in Q2 of this year, so as to optimize likelihood of success in phase II and to confirm our development strategy going forward. We believe the IA will be a key catalyst for the company and our shareholders.
After the IA is conducted, we plan to communicate our decision on next step for the program, including a rationale for adapting or not the study sample size. Because of standard timelines for FDA interaction, we will communicate our decision on study sample size before we formally discuss the IA data with the FDA. These regulatory discussions will focus on next steps for clinical development and the potential for other accelerated regulatory pathways. We plan to communicate any relevant update as appropriate following these discussions. Additionally, we continue to have strong interest from many biopharma companies on potential partnering opportunities with ATA188, and we will continue those discussions following the IA as well.
Meanwhile, we are investing significant resources in ATA188 as we are truly excited about the potential for ATA188 to transform the treatment paradigm for MS and potentially change the life of patients with this debilitating and sometimes fatal disease. I'd like now to turn the call back to the operator to begin our final Q&A portion of the call. Operator?
At this time, we'll be conducting our final question and answer session. If you'd like to ask a question, please press star one on your telephone keypad. You will hear a confirmation tone to indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment please while we pull for questions. Our first question is from Ben Burnett with Stifel. Please proceed with your question.
Hey, thank you very much. I was wondering if there's any color you can give around the futility analysis aspect of the IA. I guess confirm if there will be a futility analysis. I guess what has to happen on EDSS to trigger this? Like, does basically EDSS need to be worse on drug versus placebo? Is there anything you can just say around the alpha spend on this, even if it's just qualitative?
Thanks, Ben. AJ, do you want to take that one?
Yeah, thanks for the question, Ben. You know, in terms of the, yes, there is a futility component to the analysis. We haven't really commented on specifics related to it, apart from saying that it's extremely unlikely that we would hit futility from everything that we've modeled out. Yes, there is a futility component. In terms of alpha spend, yes, also there is an alpha spend. You know, we've discussed the type of alpha spend we should take with the FDA. Again, we haven't really commented even qualitatively on it, apart from noting that we did discuss that with the FDA. We've agreed that we need to take the alpha spend, and we have taken it.
Okay.
Does that answer?
Excellent. Thank you. Yeah. Thank you very much. If I could just ask one more on the EBV vaccine candidate. Just curious, is this a peptide-based vaccine or a nucleic acid? At this point, do you have a sense for how the antigens included in the vaccine compare to the epitopes being targeted by ATA188?
I think Jakob?
Yeah. Thanks for the question, Ben. As I mentioned, it's a multi-subunit differentiated vaccine candidate. It's really multiple epitopes that are represented in that. The preclinical data confirms the potential to stimulate both B-cell and T-cell responses. Again, our colleagues at QIMR have been part of this really extensive work that we've been doing. We think this is a more extensive targeting of EBV, which again, can generate both B-cell and T-cell responses.
Okay, great. Looking forward to learning more about that. Thank you.
Our next question is from Tony Butler with Roth Capital. Please proceed with your question.
Yes. This is really directed toward the vaccine, and it's twofold. One is, would one of the subunits include the amino acids, the small peptide which is associated with EBNA, the transcription factor? That's number one. Number two, what would you say would be the average number of B-cells in any one patient that would have or that would be EBV positive? That is to say, does that vary greatly among patients? Would you have an idea? Thank you very much.
Thank you, Tony, for your question. I'll address the first one. At this stage, we are not disclosing any specific details, but one could expect that the knowledge we have accumulated over time on better understanding, especially with the team at QIMR, what are the key element of this latent EBV infection that is causing the MS and other autoimmune disease. All this knowledge has been put into the development of ATA188 and of course the vaccine. AJ, do you want to address the second question?
Yeah, that's a really good question, and I'm not sure we're gonna have a really good answer for you. It's not really known exactly how many EBV positive cells are floating around. Apart from saying that, you know, if you're looking at the ones that we're specifically targeting, right? We're looking to go after these EBV positive, primarily B memory cells, as well as those EBV positive plasma cells. Again, that number is gonna be really small. It's hard. There's really no data that we can really point to to suggest what that number looks like.
Thank you very much.
Sure. Thank you, Tony.
Our next question is from Salim Syed with Mizuho. Please proceed with your question.
Great. Thanks again, guys. A couple from me, if I can. So Pascal or team, when you run this IA, can you just remind us what percentage of patients you need to show an improvement here to hit a p-value of 0.05? And also the same question for a p-value of 0.01. Then the second question is, which scenario do you believe that you can actually file here for accelerated approval, if you were to use this randomized controlled trial and just expand it massively, and then use the two phase IIIs that you spoke about more as a confirmatory? Thank you.
AJ, do you want to take the first question?
Sure. Appreciate the question, Salim. You know, we haven't really commented on, you know, the P values or anything to that extent. Primarily you have to remember what we're looking to do with this particular interim is that there's going to be a limited number of patients at the 12-month time point advanced. We'll have them, right? The analysis is driven by that 6-month time point. What we're really looking to do is to say, okay, when we see that 6-month time point, do we need to make any adjustment to the sample size? Or if we do make an adjustment, how do we maximize the chance of the right, you know, statistical power at the end of that 12-week timeframe? That's what we're shooting for. We wouldn't really
You know, it's not like we're necessarily looking for a specific P value at the six-month time point. We really wanna aim for making sure the right adaptation is made, if necessary, to win at that one-year time point. That's what the goal is. We have not commented on specific details, though, on, you know, the actual P values and the stats plan at this point.
Maybe to answer your second question. At this stage, it is, we'll say very unlikely that the EMBOLD study could be sufficient for a BLA submission, especially with only 80 patients to be enrolled. Whether it will ultimately depend on the data we see in the IA and the end of the phase II and further dialogue with the FDA. Your base case scenario, as we call it, has always been that this EMBOLD study is a robust, well-run phase II study that will lead to then a program of phase III studies as well as other phase II studies in other parts of the MS continuum.
Pascal, my question was more, can the phase II be expanded to one large phase III? You know, and then using the two phase III that you spoke about on the call more as a confirmatory. In what scenario would that occur?
It's very unlikely, but we can never say never when you have that type of situation. That, we'll always look at that possibility, but at this stage it's very unlikely. The base case scenario that this is a robust phase II that will lead to two phase III at least, and then other phase II. If we have an opportunity to do things differently with some accelerated path to approval, thinking about the patient first and the ability to get the product to as many patients as possible, we will certainly explore that.
Got it. Super helpful. Thanks so much.
Our next question is from John Newman with Canaccord. Please proceed with your question.
Hi, guys. Thanks for taking the question. I had one question about the follow-up patients in the phase II. You mentioned that you'll have some patients that have reached the 12-month time point. Curious if you'll have any patients that might even be beyond that. The second question I have, regarding the phase III studies, can you talk about the definition of a sustained EDSS improvement? I believe patients could show improvement at any time before 12 months, as long as it's confirmed. Just wanted to make sure that that is correct. Thanks.
AJ?
Yeah. John, would you remind me? I apologize, quickly the first question. I got the second question. I lost the first question in my brain as I was thinking.
Sure.
about how to answer your second one.
Sure. Just curious-
Oh, I remember. Sorry, John, I remembered it just now.
Okay.
You're asking how are we gonna have patients beyond the 12-month time point, right?
Mm-hmm.
Sure. At the interim? Yeah. We are actually. We'll definitely have a group of patients that are beyond that, just based on when the enrollment of the study started. We'll have, you know, a group that are 12 months and beyond, probably 18 months out, right? We'll have certain patients at that. We'll have, you know, six, nine and three months as well. Again, although we're anchoring off that six-month time point, we will factor in all of those pieces of information. Now, you also asked about, you know, kind of the definition of this of EDSS improvement. Let me try to kinda clarify it a little bit here. The way you look at EDSS improvement and you typically pick a time point, right?
For us, we're saying EDSS improvement at 12 months. If that's a confirmed EDSS improvement at 12 months, you have to have a prior time point reasonably separated, and it's usually either three months or six months before that main one that you're shooting for. In other words, some studies will say, "Hey, we wanna do a six-month confirmed to 12 or a nine-month confirmed to 12 or 12 months confirmed to 15." Those are different variants you could do, right? You've gotta have it at consecutive time points. You can't have, let's say, an improvement in 6 months, you lose it at nine and you gain it back at 12. That's not an improvement. That is not confirmed disability improvement. For our study, it's going to be 9 months and 12 months for phase II.
You have to have EDSS improvement at nine, confirmed at 12 to be called a confirmed disability improver. The concept sustained just means how long you keep it after you've confirmed it. Maybe that helps, I hope, in terms of the definitions.
The same, John, will apply to the phase III program based on the discussion we have had so far with the FDA, which will be the same thing, looking at the 12-month endpoint of confirmed EDSS improvement, which will mean to have EDSS improving at 9 and confirm at 12.
Great. Thank you.
Our next question is from Phil Nadeau with Cowen and Company. Please proceed with your question.
Hi, it's Ernie again. I guess first one quick follow on what you just said about the confirmed disability score. Does that mean that in the interim analysis, which you measure at six months, is that confirmed also from three months, or is that an isolated measurement or the first measurement?
Yeah. There, there's different ways we could do that. Just for your perspective, the data that we've reported on when we say, "Hey, the person had confirmed disability improvement at six months," for example, in the phase 1A, that was they had three months and they had six months. This 85% predictive power kind of applies to both, perspectives.
Okay. In the interim, I guess you're not measuring at three yet.
I'm sorry, say that again.
In the interim analysis, you're only measuring at six months.
No, no. In fact, what we have is we have, for the study, we have baseline, we have three months, six months, nine months, 12 months, 15 months, 18 months and so on and so forth. So that's what we have in the study. Okay? Now, the analysis itself or the interim analysis will focus on the six months at that point, just it's a question of number of patients. You need a sufficient number of patients that have achieved a sufficient follow-up to be meaningful. Based on our phase I data, and if you look in detail at the phase I data, you will see that most of the patients that were improved at 12 months started to improve at three months. There was one patient that started only at 6 months. Okay?
That's where AJ is saying that there is a diversity of experience in the phase I, but we've seen that the six-month improvement was really 85% predictive of the 12-month improvement. Since the endpoint we are very interested about for the end of the study is at 12 months, we're looking at the interim analysis time under 6 months as a prediction for the 12-month data that we expect to have at the end of the study. Does that make sense?
Okay. Got it. Yeah, no, got it. For the phase IIIs, you mentioned that the pivotal and commercial product will be the same. Is that product different than the phase II product in any way?
Yes, it is. The phase I and the phase II product have been produced for a particular manufacturing process. What we want for the pivotal and the commercial is to have this very high manufacturing yield that manufacturing efficiency that Jakob was mentioning, where we make these cells into stirred-tank bioreactors, and we believe at commercial stage we can make up to 20,000 doses from one donation.
Okay. Thank you.
Our next question is from Tony Butler with Roth Capital. Please proceed with your question.
I'm sorry for the brief follow-up, and it's back to a basic science question from earlier, if I may. AJ or Pascal or even Jakob, what is the role or do you know the role of GlialCAM as it relates to myelination or importantly maybe just to glial cell biology in general? Thanks.
AJ.
Sure. Thanks for the question, Tony. I, you know, GlialCAM is actually found kind of across a lot of different cell types in the brain. The glial cells, astrocytes, and oligodendrocytes. The oligodendrocytes are the ones that are actually responsible for myelin production. GlialCAM actually plays an incredibly important role with oligodendrocyte health. Any kind of impairment to GlialCAM is going to significantly impact oligodendrocyte. It is a key aspect of myelin health in the central nervous system. Again, it is found in multiple cell types. It's just that that particular aspect of what GlialCAM does is really significantly important for myelination.
Thank you very much, AJ. Appreciate it.
That concludes our question and answer session for today. Thank you for joining the Atara Biotherapeutics EBV and MS Day conference call. You may now disconnect.