Afternoon, everyone. Thank you for standing by, and welcome to the Atara Biotherapeutics Fourth Quarter and Full Year 2021 Financial Results Conference Call. At this time, all participants are in a listen-only mode. A question-and-answer session will follow the formal presentation. If anyone should require operator assistance during today's conference, please press star zero on your telephone keypad. Please be advised that today's call is being recorded. I'd now like to hand the call over to Mr. 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 Atara's Fourth Quarter and Full Year 2021 Results Conference Call. Earlier today, we issued a press release announcing our fourth quarter and full year financial results and operational progress. This press release and an updated slide deck are available in the Investors and Media section at atarabio.com. On today's call, members from the Atara executive team will provide an update on our financial results and operational progress, and also review our upcoming key milestones and objectives. Joining me on today's call are Dr. Pascal Touchon, President and Chief Executive Officer, Dr. Jakob Dupont, Executive Vice President and Global Head of Research and Development, Utpal Koppikar, Chief Financial Officer, Dr. AJ Joshi, Chief Medical Officer, and Dr. Kristin Yarema, Chief Commercial Officer. We will begin with prepared comments from Pascal and Jakob, then open up the call for your questions.
We would like to remind listeners that during the call, the company's management will be making forward-looking statements. Actual results could differ materially from those stated or implied by our forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's press release and the company's SEC filings. These statements are made as of today's date, and the company undertakes no obligation to update these statements. Now, I'd like to turn the call over to Pascal Touchon. Pascal Touchon.
Thank you, Eric, and thank you all for joining us this afternoon. The fourth quarter and in 2021, Atara made important progress across our three strategic priorities, tabelecleucel, ATA188 in multiple sclerosis, and our next-generation allogeneic CAR-T programs. I would like to start off with tabelecleucel and provide an update on the MAA review in Europe and our plan for BLA submission in the U.S. First, some background on tabelecleucel CMC development and comparability. As you know, over the last few years, we had to make minor changes in terms of manufacturing process between the pivotal study and intended commercial product to scale up and comply with cGMP. In order to file for regulatory approval through FDA and EMA, we have performed comprehensive studies showing analytical comparability between the pivotal study and commercial manufacturing process versions.
These comparability analyses included all 74 available product lots manufactured by Atara and covered 21 key attributes for potency, purity, and alloreactivity. For each key attribute, there is some inherent variability, even with a well-controlled and robust manufacturing process, as seen already with all approved cell therapies. In the absence of specific guidance for such a first-in-class allogeneic cell therapy, we have determined an acceptable range of variability for the values of key attributes based on the extensive and favorable clinical efficacy and safety data for tab- cell. We then applied a specific and well-established statistical methodology to demonstrate comparability between process versions for each key attribute. Minor differences on a few specific attributes were justified according to ICH guidelines in demonstrating the absence of clinical impact based on our significant and consistent clinical experience across process versions.
Following our analytical comparability studies, we believe that tabelecleucel pivotal and commercial product versions are indeed comparable. This comparability data we have discussed in a pre-submission meeting with EMA and submitted as part of our MAA filing in November of 2021. The review and the accelerated assessment is progressing as planned following receipt of EMA day 80 critical assessment report with an anticipated approval in Q4 2022. Pre-launch preparations are progressing well in collaboration with our partner, Pierre Fabre. In the U.S., we conducted very recently a type B CMC meeting in late February with the FDA to discuss and potentially align on the topic of comparability of pivotal clinical trial to commercial product. As previously noted, we believe this alignment will facilitate a BLA submission by the end of Q2 2022 as planned.
Preliminary meeting responses and discussion did not result in alignment. Unexpectedly, the FDA has initially recommended Atara conduct a clinical study with a commercial product. As I do not agree that comparability has been demonstrated. Atara has responded with additional questions to FDA in order to clarify the FDA's view and has suggested several alternative approaches to progress to a BLA submission, given the unique nature of tabelecleucel having BTD status with the potential to address an urgent and unmet medical need in an ultra-rare disease for patients with limited life expectancy and no approved therapy.
As additional background, we also filed an IND amendment in Q4 2021 with the FDA in order to use commercial product for clinical trials so that we can cover patients with appropriate HLA match using our existing inventory of commercial products instead of needing to manufacture new lots of clinical material for the ongoing studies. Following submission and review of this IND amendment by the FDA, we have started treating patients in Q4 2021 with commercial tabelecleucel product in our clinical trials and the expanded access program. This means that we are already gathering clinical data with a commercial product, and we will be able to provide such data to the FDA. Additional interaction with the agency are therefore expected, including receipt of the final type B CMC meeting minutes.
However, as a result of such preliminary feedback received from the FDA, Atara does not currently expect to file a BLA for tabelecleucel in Q2 2022. While disappointed by the FDA unexpected preliminary response on comparability, we will continue to engage with determination and confidence with the FDA on potential pathways to a BLA submission for tabelecleucel, and we plan to provide a further update during our next quarter record. Why are we confident? Tabelecleucel is a first-in-class Breakthrough Therapy Designated product that addresses urgent unmet need, as patients in second-line PTLD have no approved therapies and a very limited median life expectancy of just a few weeks to a few months.
Tabelecleucel is also a particularly unique case as its development over many years has led to the need for minor changes in the manufacturing processes to achieve GMP compliance and scale up. However, tabelecleucel clinical experience of over 300 patients, including more than 180 with EBV positive PTLD, establishes, we believe, very clearly a safe and effective range of key product attribute values, enabling determination of acceptable commercial product specifications. We are pioneers in cell therapy, and tabelecleucel has a potential to be the first of its kind, which may require a unique approach to approval, similar to what was achieved by autologous CAR-T. Further collaboration with the FDA could allow us to align on a reasonable path to submission and approval, so as to allow U.S. patients in serious need to access this potentially life-saving therapy.
I know from personal experience that bringing a transformative therapeutic innovation to patients is not always straightforward, but I feel confident that we will find a constructive way to get tabelecleucel filed and approved in the U.S. Now, moving to the rest of our pipeline. It is important first to mention that we believe the current comparability regulatory topic on tabelecleucel is specific to this product development. Indeed, this unique situation with tabelecleucel does not apply to ATA188 or our allogeneic CAR-T programs. It is also worth noting that as a result of our CMC development history and regulatory interactions with tabelecleucel, we have already incorporated several learnings and have adjusted our approach going forward to optimize success with regulatory agencies for other pipeline products and our platform. Turning now to ATA188, our allogeneic MS program.
Momentum continues to build for this potentially game-changing product within both the medical and investor community. Recently, two separate landmark publications in Science and Nature presented what we believe is compelling new epidemiologic evidence that EBV is the leading cause of MS, and mechanistic evidence showing how EBV infection can initiate and propagate the autoimmune attack on the brain in MS. As a result of the excitement generated by these publications, we are seeing increasing interest from patients, MS experts, and potential partners. Further, building on this increasing momentum, we are also pleased to announce that we will be hosting an Atara EBV and MS Day with investors and analysts in late March, prior to conducting the interim analysis in Q2 of this year.
The Atara EBV and MS Day will cover all aspects of the causal association between MS and EBV, the rationale of addressing this disease as its root cause through precision therapy like ATA188, and current data and development plans for ATA188. We hope this event will continue to further build excitement and understanding around the potential of our approach to create significant value for patients, for Atara, and for shareholders prior to conducting the IA in Q2. As we communicated in January, FDA granted Fast Track designations in both non-active SPMS and non-active PPMS populations, and we are continuing to make good progress with enrolling the phase II randomized double-blind placebo-controlled EMBOLD study, evaluating the efficacy and safety of ATA188 in patients with progressive MS, with patient number 80 expected to be enrolled soon after the planned interim analysis.
With respect to the interim analysis for the ATA188 EMBOLD study, we are on track to conduct the IA in Q2 of this year so as to optimize the likelihood of success in phase II and to confirm our development strategy going forward. After the IA is conducted, we plan to communicate our decision on next steps for the program, including rationale for adapting or not the study sample size. We also plan to continue a productive dialogue with the FDA following the IA, and thus we will likely communicate our decision on next steps for the program before we formally discuss the IA data with the FDA. Our planned discussions with the FDA following the IA will include next steps on the development pathway and potentially other accelerated pathway applications such as RMAT. We will communicate any relevant updates as appropriate following these discussions.
Additionally, we continue to have strong interest from large pharma companies on potential partnering opportunities with ATA188, and we will continue those discussions following the IA. Our MS strategy is focused upon ATA188, but it also includes developing an EBV vaccine, leveraging our unique knowledge of the link between EBV and autoimmune disease like MS. To this end, we are pleased to announce that pre-clinical work is progressing on Atara's very own EBV vaccine. For some time, we've been collaborating with our vaccine expert, QIMR, with encouraging pre-clinical studies, and we are currently advancing into IND-enabling studies. We will have more to say about this program at our upcoming Atara EBV and MS Day.
Last month, we were also pleased to announce our strategic partnership with FUJIFILM Diosynth Biotechnologies to acquire our ATOM manufacturing facility in Thousand Oaks for $100 million upfront, which is on track for an anticipated close in April. As part of the transaction, we will enter into long-term supply agreement with Fuji, which will provide Atara with access to expert cell therapy manufacturing staff, flexible capacity, and specific capability to support our pipeline. Additionally, we expect to benefit from reduced operating expenses going forward over time. Importantly, after the close of the deal, we retain a talented technical operation team, including process science, quality assurance, and supply chain logistics. We'll also continue to invest in our research, product design, manufacturing, and asset development for early stage and scale-up phases. We are excited to work closely with Fuji going forward.
I would like also to highlight that any possible delays in tabelecleucel U.S. approval will not impact this partnership, as we built in the necessary flexibility in terms of our supply needs. Moving now to our financials. With regard to our cash position and runway, we ended the fourth quarter of 2021 with $371 million in cash. This includes $48 million from the sale of shares of common stock through our ATM facility in the quarter, and a $45 million upfront payment received in the Pierre Fabre commercialization agreement. We believe cash as of December 31, 2021, together with the anticipated $100 million payable to Atara upon closing of the strategic transaction with FUJIFILM, will be sufficient to fund the company's planned operations into the fourth quarter of 2022.
I will now turn the call over to Jakob to give you more details on ATA188 development and our CAR-T program. Jakob?
Thank you, Pascal. With regard to ATA188, our product candidate for multiple sclerosis, recently there were landmark publications in the journal Science and Nature which presented what we believe is undeniable evidence that EBV is a leading cause of multiple sclerosis and a required trigger for the disease. Specifically, MS may be mediated by b- cells and plasma cells that are infected with EBV. In the Science paper, it was shown that the risk of MS increased 32-fold after infection with EBV, but was unchanged after infection with other viruses. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after Epstein-Barr virus seroconversion. Adding to the EBV MS epidemiological connection, scientists detailed in Nature how EBV shares or mimics certain peptide sequences with a healthy brain protein called GlialCAM.
The damage occurs when the immune system b- cells that have been infected by EBV produce antibodies that target EBV, and unfortunately, these antibodies also attack the self brain proteins. In basic terms, it's a case of mistaken identity. The antibodies produced target both EBV and central nervous system proteins, leading to brain inflammation, demyelination, and axon destruction, which are all hallmark features of multiple sclerosis. We are very excited about these findings, which were widely publicized, including in the popular press, as well as among the neuroscience community, and view it as further validation of our approach for ATA188 to target EBV in MS patients to improve their outcome. As Pascal noted, after these studies were published, there has been an uptake in inquiries by MS investigators and patients, as well as potential ATA188 partners.
At our upcoming MS Day in late March, we look forward to diving deeper into these studies and the implications of what it might mean in the context of treatment with ATA188. As we look forward to the results of the randomized placebo-controlled phase II EMBOLD study, I wanna first remind everyone of the encouraging data we've seen thus far in phase I. Recall, in our phase I data, an open-label extension of 24 patients, we saw seven patients demonstrate sustained EDSS improvement, with 13 showing stability through the participation of the study. Remarkably, 20 of 24 patients either improved their EDSS or were stable, which is contrary to the expected decline over the natural course of this disease. Also, as a reminder, we have agreed with the FDA that the primary endpoint of the phase II EMBOLD study will be sustained EDSS improvement at 12 months.
To this end, the key data point we will analyze at the interim analysis will be sustained EDSS improvement at six months. As patients continue to enroll at different times in the study, there will be a range of treatment durations at the time of the IA. Some patients will have more than six months, some will have less than six months. We will take a look at all these data when making our decision. We have confidence a six-month time point for sustained EDSS improvement is meaningful. Based on our phase I data, patients achieving sustained EDSS improvement at six months is over 85% predictive of achieving sustained EDSS improvement at twelve months. As a reminder, we showed 33% sustained EDSS improvement at six months in the two high-dose cohorts in the phase I study.
The results of the IA will support determining the sample size necessary to achieve a target conditional power at the end of a study, and it will inform our phase III design and planning. After the end of phase II, we plan to conduct pivotal phase III studies in both non-active SPMS and PPMS populations. One study will focus on non-active SPMS, where there's no approved therapies in the U.S. or EU, and a separate study will focus on non-active PPMS, where there are very few treatment options of limited efficacy. Now turning to our CAR-T programs. Recently, we announced that our partner for autologous ATA2271, namely Memorial Sloan Kettering, notified the FDA of a fatal serious adverse event associated with a patient treated in the ongoing phase I MSK-conducted dose escalation study.
As was noted, MSK voluntarily paused enrollment of new patients in the study on a temporary basis. This is a complex case, and MSK is in the process of further evaluating the occurrence. We anticipate providing an update in the next several weeks following further investigation and discussion with MSK. Our thoughts are, of course, with the patient and their family. The temporary pause of ATA 2271 study enrollment does not impact the IND-enabling work currently underway to advance ATA 3271, a separate off-the-shelf allogeneic CAR-T therapy targeting mesothelin using next generation PD-1 DNR and 1XX CAR technologies for patients with advanced mesothelioma, for which we anticipate an IND filing in the fourth quarter of this year. Now, ATA 3271, ATA 3219, tabelecleucel, and ATA 188 all utilize Atara's allogeneic EBV t-cell platform.
The safety and tolerability for which has been validated by clinical studies and the experiences in approximately 400 patients in various disease areas, particularly with no observed cytokine release syndrome to date. Hence, there's no impact of this ATA 2271 event whatsoever on our clinical studies with tabelecleucel or ATA188. As a reminder, our approach to CAR-T does not require TCR or HLA gene editing and presents a differentiated approach that retains the endogenous T-cell receptor. This has been shown in academic studies to increase persistence, durability, and trafficking of the cells. Additionally, I'd like to highlight that today is Rare Disease Day. A day in which we raise awareness of patients living with rare disease and the urgency with which patients need life-saving therapies.
Today, on Rare Disease Day, we recognize how vital the efforts are to find new transformational therapies for patients with PTLD and other rare diseases. In closing, I'd like to extend my gratitude to the Atara staff, our collaborators, and the patients involved in our studies. We're working together as a team with purpose and with hope as we chart new territory for allogeneic T-cell therapies. We acknowledge the challenges, yet are committed to bringing transformational new therapies to patients in need. Now I'd like to turn the call back over to Pascal.
Thank you, Jakob, and thank you all again for joining us this afternoon. We've covered a lot of ground on today's call, and before we get into Q&A, I want to take a few minutes to summarize what we discussed with regard to tabelecleucel in the U.S. At this time, the FDA's recommendation is preliminary, and we are currently exploring several alternative pathways with FDA to enable the filing of a BLA based on data from the ongoing ALLELE pivotal study. Tabelecleucel is a novel product and has the potential to save the lives of patients with an otherwise fatal disease. We are confident that we can find a reasonable pathway in collaboration with the FDA to give U.S. patients access to this potentially transformative therapy. I'll now turn the call back to the operator to begin the Q&A portion of the call. Operator?
At this time, we will be conducting a question and answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary for you to pick up your handset before pressing the star keys. One moment while we poll for questions. Our first question comes to the line of Salim Syed with Mizuho. You may proceed with your question.
Great. Good afternoon, guys, and thanks for all the color. Two for me, if I can. One on ATA188 and one on additional indication that I think you were alluding to in the press release, but I just wanted to confirm. Pascal or Jakob, AJ, one of the bear cases right now on the stock obviously is that the interim analysis is not gonna be something that investors can really understand what this data is looking like because the communication will just be qualitative. I just wanted to tick through, if I could, just a few points here, if these are at least in the cards of how you're thinking about communicating this data.
A, is it possible that you're gonna use some sort of cross-trial comparison or reference to the phase I treatment data or some cross-trial comparison of placebo? B, could we expect, is it in the cards that a pharma partnership is gonna come simultaneously with the IA communication? C, is an RRMS trial start something that you're also considering simultaneously with the IA announcement? Just a second question, is just on a recent publication in Cell talking about EBV reactivation for long COVID, and I'm just wondering if that's an indication that you are looking at long COVID given your EBV platform. Thank you.
Thank you, Salim. I'll start on your first question, then Jakob will handle the second one. In terms of the IA, what we say that we'll be communicating our decision related to the study sample size and the rationale of that. We have not given any more specifics in the sense that the specifics will depend very much on the type of data that we have access to and the consequence of the readout of this data. We understand the questions from the investors community and will make sure that we are as clear as possible to our communication at the time of the IA. Now, you ask about pharma partnering.
Our current plan, and I think that's what we try to express in the prepared remark, is that there will be the time of the IA and the communication following this interim analysis based on our internal decision, following access to some specific data. That's kind of the first time of communication. Then there will be in parallel discussion with potential partners that will have access under CDA to some type of data to be able to move forward in partnering discussions. As we said, we have a number of very interested parties right now that we're discussing with, but they will have access only after the IA and decision and only to part of the data.
In parallel, we will also engage with the FDA to be able to work with them on the next steps of development and a potential additional accelerated path such as RMAT. The best way to look at that, Salim, is to say communication after the IA, once a decision is being taken about the decision and the rationale, then some update at some stage on interaction with the FDA. At some stage, hopefully a discussion on partnering and an update on that. As you know, this type of update is only at the time of a deal is being executed, which always takes a few months following a particular event. That's what you should expect from that point of view. Now on the RMS study, maybe AJ you want to say a few words about that.
Sure. Excuse me. Sure. Salim, I think, you know, from the RMS perspective, that's something we've been contemplating for a while. As you know, we would expect ATA188 to work really across any type of multiple sclerosis. We've actively kind of assessed the right type of RMS study design, and that is something we are contemplating fairly actively right now.
Regarding the EBV possible opportunity for additional treatment, Jakob?
Yeah, absolutely. Salim, thank you for raising this issue of long COVID and the potential role of EBV here. We've been following this story with a lot of interest as well. As we know, with the pandemic, up to 30%-70% of COVID patients will suffer from long COVID. This is becoming a really emerging health issue in the population. There have been some really high-profile publications of late. Salim, as you mentioned, there's the Cell publication in January of this year by Su and colleagues, and it was really interesting. They looked at 309 patients and looking for various underlying causes for long COVID or PASC. They actually found that one of the four risk factors for developing PASC was actually reactivation of latent EBV.
It's pretty interesting when you consider some of the symptomatology of long COVID, where you have memory lapses, you have fatigue, which are not unlike some of the things that you see with in MS, where again, EBV is a driver. Then there is another publication of note by Gold and colleagues in Pathogens that described in a small study, but two-thirds of patients with long COVID had EBV reactivation, which compared to only 10% of control patients. It looks like long COVID, certainly, there is a risk there of developing long COVID with EBV reactivation. That's certainly where a product like tabelecleucel could come in. To your further query, we have been in discussions with leading academic institutions regarding this topic, and this has been going on for several months.
We're not in the position now to announce any active studies of this sort. We're certainly exploring this possibility and think that this could be quite interesting to explore further with academic groups.
Very helpful. Thanks so much, guys.
Our next question comes from the line of Tessa Romero with JP Morgan. You may proceed with your question.
Hey, guys. Hope everyone is doing well. Thanks for taking our questions. The first one is on tabelecleucel. To confirm, has the EMA agreed that the pivotal and commercial materials are comparable? For the FDA, based on recent interactions here, do you know exactly why they don't see comparability between the two products? Are there specific attributes that they disagree with? I have a follow-up, if I could.
Thank you, Tessa. First question, maybe Jakob, and I'll take the second one.
Absolutely. Thanks for the question, Tessa. As Pascal has described, we performed extensive studies showing analytical comparability between tabelecleucel process versions between the pivotal and the intended commercial one. We've shared all of this comparability data with EMA through the MAA filing that we submitted in November of last year, and this filing is currently under review through the accelerated assessment mechanism in Europe and is proceeding according to plan. Now, we did receive, as Pascal mentioned, the EMA day 80 critical assessment, and we are looking at an anticipated approval in Q4 of this year. The preliminary report in that day 80 critical assessment indicates acceptance of comparability between process versions in that EMA assessment.
To your second question, Tessa, I think the, as what we mentioned, there is some inherent variability even with a well-controlled and robust manufacturing process for all cell therapies, including those approved. We are confident that in the absence of specific guidance, we have determined the range of variability for the values of key attributes based on this extensive and favorable clinical efficacy and safety data that we have available for tabelecleucel and that we've presented and published across different forums. Now, what we've done is that we've applied specific and well-established statistical methodology to demonstrate comparability between process version for each attribute. There have been minor differences on a few specific attributes.
What we did with the FDA and EMA, that we justified these minor differences according to ICH guidelines, to demonstrate that there is no clinical impact, whether on safety or efficacy of these minor differences between some, on some key attributes between process version. We had consistent clinical experience across process version. Discussion with the FDA is really related to these aspects. Does this answer your question?
Yeah, that's really helpful. Just thinking just quickly on the MS program here, as a follow-up to the prior question. I guess, will we have a directional sense for how the data is trending at the time of the IA, or is that a question that you're willing to answer at this time or no?
That will certainly be nice to have, to be able to communicate more than to have. We'll have it, but to be able to communicate at the time. What we say is that it's too early to exactly be very specific about what we will be able to communicate. As we said in the past, we still want to preserve the integrity of that study, especially for discussion with the agency, with the FDA. At this stage, we cannot give any more specifics, but again, our intent will be to be as specific as possible, as clear as possible within the context at the time of our communication on our next step following the IA.
Okay. Got it. Thanks so much, guys.
Thank you, Tessa.
Our next question comes from the line of John Newman with Canaccord. You may proceed with your question.
Hi, guys. Thanks for taking the question. Just had two questions here. The first one is regarding the interim analysis for ATA188. Assuming based on prior comments that at least internally, you will be able to assess sustained EDSS improvement at six months, but you will also have certain number of patients that have moved beyond six months, for example, to nine or 12 months. Just wondering if those data at least will be able to be shared internally with partners and the FDA. Second question I have on tabelecleucel. Do you believe that there are differences in the analytical comparability method that could still be adjusted, or are you now at a point where you may be considering just giving the FDA additional clinical data with the commercial material? Thanks.
Okay. I'll answer the first question, which is more about communication and Jakob, you'll take the second one, I guess. On the first question, the intent is indeed, John, to communicate under confidentiality agreement to selection of potential partners, as well as to the FDA, the data from the interim analysis. You're right to say that even though the main criteria for determining the conditional power of the study is going to be the EDSS improvement at 6 months, because it's 85% predictive of the ultimate endpoint at 12 months. We will have a number of patients with 9, 12, even up to 18, or whatever months. I think that is something that will be important in terms of the overall perspective on the study.
Now, we will also have access to data on MRI and MTR, as well as some biologic markers. All that will help us to put together a particular package of data to be communicated to potential partner and to the FDA with different objectives, with the two different group of organization that would get access to part of the data under CDA. Now, on the second question on tab-cel, maybe Jakob, you can elaborate a bit on our plan for alternative path with the FDA.
Yeah, absolutely. John, thanks for the question. What we're doing, after the type B meeting that we recently had with the agency, we asked a series of additional questions for clarification on the FDA position, and we will get those final minutes within due time here. That would be very interesting. We've also made additional proposals to the agency where we believe that there are other ways to answer the questions that the FDA have, rather than embarking upon a new clinical trial. We think that we have a range of options. We are in active dialogue with the FDA and again, we'll get those official minutes. But we've also made a series of other proposals to the FDA that we think could resolve this issue.
More particularly, I think, to come back to your question, John, here. We think that there are different aspects that are worth discussing in data. One is that we have, as we said, established a safe and effective acceptable range of values for each attribute. So we have ways to establish the specification of a commercial product that will support a safe and effective product. We want to discuss how to establish range of specification based on the clinical experience with different values of key attributes. We also have the data that we have started to generate by already having commercial product in the clinic treating patients, which is a great way to generate clinical data.
Of course, we also are proposing to do some continuous monitoring in a post-marketing setting, which may be another way to address some questions about adding further clinical data with the commercial product. Does it answer your question?
Yes. Thank you.
Our next question comes from the line of Phil Nadeau with Cowen and Company. You may proceed with your question.
Hi, this is Ernesto Rodriguez-Dumont for Phil. Thank you for taking our call or question. I guess first I have a clarification. This decision, was that a change of mind from the FDA, or was this a reaction to the new analysis?
In fact, it was, as I said, unexpected. We were surprised by that, preliminary recommendation to say that they do not agree with comparability and suggesting a clinical trial with a commercial product. We are very surprised by that. Because as you know, throughout the past two quarters, we've given regularly during our quarterly call, a very transparent update of our progress on this aspect of comparability between pivotal and commercial product with the FDA. We've explained that initially, we had submitted data on 50 lots for each product version with a statistical power with 95% confidence interval to demonstrate equivalence. Then the FDA say that they wanted to see more, and they wanted in fact to see all the manufacturing batches.
We presented and we had a CMC Type B meeting in October with data on all 74 lots that represented the vast majority of the total lots produced. The FDA asked for additional questions. We provided the answer to these additional questions in an IND amendment at the end of the year. We had another Type B briefing book for the very recent IB meeting, where we put together not only all these statistical analysis, not only all these analytical comparability data, but also putting that in perspective of the clinical data according to ICH guidelines. The debate has been going on for some time, but we always thought that we were providing the FDA with the answers to their questions.
The amount of data that we have to demonstrate comparability is quite impressive in terms of both the analytical data and the correlation and linked with the clinical data and very consistent clinical data in terms of efficacy and safety across product versions. Across more than 300 patients treated and more than 180 with EBV positive PTLD, which I remind you, is an ultra-rare disease. It's quite impressive to see the amount of data that we provided them with. That's why we were very surprised of their preliminary position.
How is that decision that their rationale behind that decision different than their agreement to allow you to use the commercial product for the current studies? Because you're treating patients with that commercial product.
Yes.
What's different there?
It's a different process, but you're right to point that out as something interesting, but it's a different process. I mean, when we ask them to be able to use a commercial product to treat patients, that has been through an IND amendment with providing data for an IND amendment. As usual, when they review this data, if they don't react within a certain period of time, you can start to treat patients. We started to treat patients, including in single patient use that they approve patient per patient. That has been one process. In parallel, there is this process of demonstrating comparability for the BLA filing, which is of course a different process having different type of questions from the FDA.
On one hand, they have allowed us to be able to treat patients with a commercial product. I think that's very important because we are accumulating data in terms of efficacy and safety of that commercial product. On the other hand, they have not agreed on comparability between commercial and pivotal at this stage.
Okay. Just one final quick one. They mentioned they recommended a clinical study. Did they give you any details about what that study may require? How confident are you that that decision, that preliminary recommendation can be swayed?
Yeah, no, they are proposing to have a dialogue with us on that. As we said, we have proposed alternative paths to the BLA submission because we think that there are other ways to answer FDA questions. That's what we are discussing in an active dialogue with them now, is this alternative path to a BLA submission that will rely upon the clinical data from the ALLELE pivotal study, as well as all the other elements I mentioned earlier on related to how do you establish specification for such a commercial product based on the range of acceptable values of the key attributes. As well as this, new clinical data that we are accumulating on the commercial product in the various clinical trials and extended access program.
All right. Thank you. Thank you.
It's an active dialogue, and we look forward for further collaboration with the FDA to find a solution.
Thank you.
Our next question comes from the line of Benjamin Burnett with Stifel. You may proceed with your question.
Hi, this is Carolina Ibanez on for Ben Burnett. Thank you for taking our question. If I understood you well in your prepared remarks, you stated that you plan to provide an update in the next few weeks on your investigation into the fatal serious adverse event that occurred in the phase I study of ATA2271. Can you share at this point the level of cell expansion observed in the treated patient who died? In the context of this fatal event, could you review the rationale behind the use of 1XX co-stimulatory domain over a more validated construct such as CD28? Thank you.
Thank you, Carolina. Jakob, do you want to address these questions?
Yeah, absolutely. We are communicating obviously with Memorial Sloan Kettering on this particular patient, and we will be getting more information on the workup that Memorial is doing for this patient over the course of the coming weeks. We will have further updates for you in this regard. As we mentioned, the Sloan Kettering did their duty, and they obviously put a temporary hold on enrollment here, and then they shared the information with the FDA and with us, and the FDA has supported the decision there. Now we are getting data in on things like cytokine profiles and cell expansion and so forth as well. We'll be able to provide more detail on this particular patient over the course of the coming weeks.
Related to the 1XX domain, that's something, as you know, that we've been using at this stage in different constructs of our allogeneic CAR-T program as well as in the case of 2271, the autologous mesothelin CAR-T. This is a costimulatory domain that has already been used in a clinic. I mean, because this was not licensed exclusively to Atara. You probably know that this domain has also been licensed to Takeda, to Fate, in addition to Atara, and there are other program in the clinic, and so far we've not heard about any safety aspect of this program or safety issue with this program in the clinic. Again, the case of this unfortunate case with a patient with 2271 requires some further investigation because it's a very complex case with many confounding factors.
We need to do that in a very good way and deep way with our partners at MSK. We will communicate in proper time when we have a better understanding. It's a very complex case, a lot of confounding factors, a very advanced patient in fourth line of treatment. We need to have a better understanding of these different aspects before MSK can make a conclusion and we can communicate about that conclusion about the potential cause of these particular unfortunate events.
Just one other comment regarding 1XX. We do believe that construct, which is really a next generation co-stimulatory domain, has advantages over CD28, CD3ζ, or, you know, 4-1BB per se, where the behavior of this co-stimulatory domain in terms of persistence of cells in vivo expansion, you know, some of the phenotypic aspects of the CAR-T cells are really favorable relative to the first generation. We think that this particular design from Dr. Michel Sadelain at Memorial Sloan Kettering really does have some advantages over the first generation constructs.
Any further question.
Understood. Yes, perfect. Thank you again.
Thank you.
Our last question comes from the line of Tony Butler with Roth Capital. You may proceed with your question.
Thanks very much. Pascal, the notion of the FDA not agreeing with comparability on tabelecleucel would not therefore imply that there would be a difference in safety and efficacy of the product. I assume that would be true. That's part A. Part B is, it strikes me though, you know, I guess I'd have to ask how rapidly is the expansion cohort in which the commercial line in the newer product, the commercializable product, is being utilized. Wouldn't that be sufficient, at least at some patient level, to solve the questions at the agency? That's question one. Question two is what gives you confidence that ATA188, for example, would not be affected in any way, either as this progresses and/or gets solved or just comes to a standstill or just takes longer time?
Thanks very much.
Thank you, Tony. Jakob, you take the first question, take the last one.
Absolutely. Thank you, Tony. I will say that we now have a lot of clinical experience. You know, Pascal mentioned this, where we've treated over 300 patients through the academic and the Atara program. Over 180 patients with EBV positive PTLD. It's a very robust clinical data set there. The safety is really quite good. We don't see organ rejection. We don't see graft versus host disease beyond background. We don't see cytokine release syndrome. This has really been true across the various process versions. As you saw at ASH, the safety profile is really quite good.
That comes with really outstanding efficacy, where once again, if you look at the pivotal ALLELE data at ASH, we see high response rates, 50%, you know, for these patients that have no other treatment options, and that's a durable response. We believe that some of these patients treated years ago at Memorial Sloan Kettering are actually cured of this fatal disease. We know what the specifications are for the various process versions there. There is great consistency in that clinical data. We believe it's a very reassuring data set. We also, as mentioned, have submitted this data to EMA as well, and they have preliminarily come to the conclusion of comparability. This is an active dialogue with the FDA.
We do think that focusing on the clinical data in this very high unmet need population in a BTD therapy is really important, and we believe it's quite consistent as well. In terms of you mentioned this expansion of the cohort of patients with the commercial product. We think it's very exciting. We're in the clinic with the commercial product, and as mentioned, we did have that IND that went through the FDA here in December of last year, and we are actively treating patients on expanded access, as Pascal mentioned, also on ALLELE, also on the 205 study. We think that this is reassuring that we'll be able to provide this data as well. These are the types of alternative proposals that we are making to the FDA as we continue our negotiations.
Again, this is a very active area of discussion.
Yeah, I will add, Tony, that on top of having accumulating our clinical data with the commercial product, we have already significant clinical data with the different values of the key attributes that are part of the commercial product. That's something that is important to have in mind, that more than 300 patients have been treated with tabelecleucel, among the 180-plus patients have been treated with tabelecleucel for EBV-positive PTLD, there have been different level of values for key attributes. We have that range, and the commercial product is within that range. We have clinical experience already with different process versions, but of the specific value of key attributes that shows efficacy and safety. That's what make us extremely confident that we'll find a way forward.
Now, your questions on ATA188 is and why do we think there is no particular impact on this development. First of all, tabelecleucel, again, is a very special case. It's been developed over many, many years, different process versions, and there have been these minor changes across those versions. If you think about it, if we have the same process version between pivotal and commercial, we won't have that debate about comparability between the two. So that's what is part of our plan for ATA188, is to have that possibility to have the same process and material used in phase III as in commercial supply. The other aspect that we've learned a lot of this interaction with the FDA, and we know better now how to, moving forward, how to address some of the potential questions they may have in the future for a new product.
I think this learning and this ability to have phase III and commercial supply with the same process versions makes us also extremely confident that this particular debate on comparability we're having right now on tabelecleucel, which is again a very specific case with the FDA, should not be an issue for ATA188 and the rest of the pipeline. Does it answer your question, Tony?
Yes, sir, Pascal. Thanks very much. Thank you, Jakob.
Thank you.
That concludes our question and answer session for today. Thank you for joining the Atara Biotherapeutics fourth quarter and full year 2021 financial results conference call. You may disconnect your lines at this time. Thank you for your participation, and enjoy the rest of your day.