Atara Biotherapeutics, Inc. Q4 FY2021 Earnings Call

Good afternoon, everyone. Thank you for standing by and welcome to 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. I’d now like to hand the call over to Mr. Eric Hyllengren, VP of Investor Relations and Finance at Atara Biotherapeutics. Please go ahead, sir.

Thank you, operator. Good morning, 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 corporate 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. Pascal?

Thank you, Eric, and thank you all for joining us this afternoon. In the fourth quarter and in 2021, Atara made important progress in the course of three strategic priorities that center around ATA188 in multiple sclerosis and our next generation allogeneic CAR T programs. I would like to start off with tab-cel and provide an update on the MAA review in Europe and our plan for BLA submission in Europe. First, some background on tab-cel CMC development and compatibility. As you know, over the last few years, we had to make minor changes in terms of the manufacturing process between the pivotal study and the intended commercial product to scale up and comply with CGMP in order to find regulatory approval from FDA and EMA. We have performed comprehensive studies showing analytical comparability between the pivotal study and the 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-cel. 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 significant and consistent clinical experience with both process versions. Following our analytical comparability studies, we believe the tab-cel pivotal and commercial product versions are indeed compatible. This comparability data, we have discussed in the pre-submission meeting with EMA and submitted as part of our EMEA filing in November 2021. The review and accelerated assessment is progressing as planned. Following receipt of EMA Day 80 critical assessment report, we expect an anticipated approval in Q4 2022. Pre-launch preparations are progressing well, in collaboration with our partner PSR. In the US, we conducted a BCMC 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 these alignments will facilitate the BLA submission by the end of Q2 2022, as planned. Preliminary meeting responses and discussions did not result in alignment and, unexpectedly, the FDA has initially recommended Atara conduct a clinical study with the commercial products, as they do not agree that comparability has been demonstrated. Atara has responded with additional questions to the FDA in order to clarify their view and has suggested several alternative approaches to progress to a BLA submission, given the unique nature of tab-cel having BTD status with the potential to address an urgent 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 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 the IND amendment by the FDA, we have started treating patients in Q4 2021 with the commercial tab-cel 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 BCMC meeting minutes. However, as a result of the preliminary feedback received from the FDA, Atara does not currently expect to file a BLA for tab-cel in Q2 2022. While disappointed by the FDA’s unexpected preliminary response on comparability, we will continue to engage with determination and confidence with the FDA on potential pathways to BLA submission for tab-cel and we plan to provide a further update during our next quarterly call. Why are we confident? Tab-cel is the first-in-class product that addresses urgent unmet needs, as patients in this category have no approved therapies and very limited median life expectancy of just a few weeks to a few months. Tab-cel is also a particularly unique case, as its development over many years has led to the need for minor changes in manufacturing processes to achieve GMP compliance. With clinical experience from over 300 patients, including more than 180 with EBV+ PTLD, we believe, very clearly, a safe and effective range of key product attributes values, enabling determination of acceptable commercial product specifications. We are pioneers in cell therapy, and tab-cel has the 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. Furthermore, collaboration with the FDA could allow us to align on a reasonable path to submission and approval to allow 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 straightforward, but I feel confident that we will find a constructive way to get tab-cel filed and approved in the US. Now moving to the rest of our pipeline, it is important first to mention that we believe the current comparability regulatory topic on tab-cel is specific to this product development. Indeed, this unique situation with tab-cel 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 tab-cel, we have already incorporated several learnings and 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 publications in Science and Nature presented what we believe is compelling new epidemiological 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. The 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 for 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 for 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, the FDA granted Fast Track designations in both non-active SPMS and non-active PPMS populations, and we are continuing to make good progress with an all-in Phase 2 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 2 and confirm our development strategy going forward. After the IA is conducted, we plan to communicate our decision on the next steps for the program, including the rationale for adapting or not adapting the study sample size. We also plan to continue a productive dialogue with the FDA following the IA, and 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 EMA D. We will communicate any relevant updates as appropriate following these discussions. Additionally, we continue to work on interest from large pharma companies on potential partnering opportunities with ATA188, and we will continue this discussion following the IA. Our MS strategy is focused on ATA188, but it also includes developing an EBV vaccine leveraging our unique knowledge of the link between EBV and autoimmune diseases like MS. To this end, we are pleased to announce that preclinical work is progressing on our very own EBV vaccine. For some time, we’ve been collaborating with a vaccine expert on encouraging preclinical 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 the ATOM manufacturing facility in Southern Oaks for 100 million upfront, which is on track for an anticipated close in April. As part of the transaction, we will enter into a long-term supply agreement with FUJIFILM, 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 will retain a talented technical operations team including process science, quality assurance, and supply chain logistics, and will also continue to invest in our research, product design, manufacturing, and assay development for early-stage and scale-up phases. We are excited to work closely with FUJIFILM going forward. I would also like to highlight that any possible delays in tab-cel US approval will not impact this partnership as we build 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 for the ATM facility in the quarter and 45 million upfront payments received in a 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 programs.

Thank you, Pascal. With regard to ATA188, our product candidate for multiple sclerosis, recently there were landmark publications in the journals 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 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 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 viewed as further validation of our approach for ATA188 to target EBV in MS patients to improve their outcomes. 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 EBV and MS Day in late March, we look forward to diving deeper into the 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 2 EMBOLD Study, I want to first remind everyone of the encouraging data we’ve seen thus far in Phase 1. Recall in our Phase 1 data, an open-label extension of 24 patients, we saw seven patients demonstrate sustained EDSS improvement with 13 showing stability through their participation in 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 2 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, and we will take a look at all this data when making our decision. We have confidence that the six-month time point for sustained EDSS improvement is meaningful. Based on our Phase 1 data, patients achieving sustained EDSS improvement at six months is over 85% predictive of achieving sustained EDSS improvement at 12 months. As a reminder, we showed 33% sustained EDSS improvement at six months in two high-dose cohorts in the Phase 1 study. The results of the IA will support determining the sample size necessary to achieve a target conditional power at the end of the study and then inform our Phase 3 design and planning. After the end of Phase 2, we plan to conduct pivotal Phase 3 studies in both non-active SPMS and PPMS populations. One study will focus on non-active SPMS where there are no approved therapies in the US 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, specifically Memorial Sloan Kettering, notified the FDA of fatal serious adverse events associated with a patient treated in the ongoing Phase 1 study. Memorial Sloan Kettering conducted a dose escalation study. MSK voluntarily paused enrollment of new patients in the study temporarily. 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 on ATA2271 study enrollment does not impact the IND enabling work currently underway to advance ATA3271, a separate off-the-shelf allogeneic CAR T therapy targeting Mesothelioma using next generation PD1DNR and 1XX CAR technologies for patients with advanced mesothelioma for which we anticipate an IND filing in the fourth quarter of this year. Now ATA3271, ATA3219, tab-cel, and ATA188 all utilize Atara’s allogeneic EBV T-cell platform, the safety and tolerability for which has been validated by clinical studies and 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 ATA2271 event whatsoever on our clinical studies with tab-cel 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 diseases 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 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.

Thank you, Jakob, and thank you all again for joining us this afternoon. We’ve covered a lot of ground on today’s call. Before we get into Q&A, I want to take a few minutes to summarize what we discussed regarding tab-cel in the US. At this time, the FDA’s recommendation is preliminary and we are currently exploring several alternative pathways with the FDA to enable the filing of the BLA based on data from the ongoing ALLELE pivotal study. Tab-cel 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 US patients access to these potentially transformative therapies. I will now turn the call back to the operator to begin the Q&A portion of the call.

Our first question comes from Salim Syed with Mizuho. You may proceed with your question.

Great. Good afternoon, everyone, and thank you for the insights. I have two questions, one regarding ATA188 and another about the additional indication mentioned in the press release, which I wanted to confirm. So, Pascal or Jakob, AJ, one of the concerns surrounding the stock is that the interim analysis may not provide clear understanding for investors, as the communication will likely be qualitative. I would like to go over a few points regarding how you plan to communicate this data. First, is there any possibility of using cross-trial comparisons or referencing Phase 1 treatment data or comparing it to placebo? Second, can we anticipate that a formal partnership announcement might happen at the same time as the interim analysis communication? Lastly, are you considering starting an RRMS trial simultaneously with the interim analysis announcement? For my second question, I'm curious about a recent publication discussing EBV reactivation in relation to long COVID. Is this an indication that you're exploring long COVID in light of your EBV platform? Thank you.

Thank you, Salim. So I’ll start on your first question, then Jakob will answer your second one. In terms of the IA, what we say is that we’ll be communicating our decision related to the study sample size and the rationale behind that. We have not given any specifics, as 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. But we understand the questions from the investor community and we’ll make sure that we are as clear as possible in our communication at the time of the IA. Now, you asked about our partnering current plan. I think that’s what we tried to express in the prepared remarks, that there will be, at the time of the IA, a communication following these interim analyses based on our internal decisions, following access to some specific data. There will also be parallel discussions with potential partners that will have access under CDA to some type of data to move forward in partnering discussions. As we said, we have a number of very interested parties right now that we are discussing with, but they will have access only after the IA decisions and only to part of the data. And then in parallel, we will also engage with the FDA to work with them on the next steps of development and potentially other accelerated paths such as EMA D. So the best way to look at that, Salim, is to say communication after the IA, once a decision is made regarding the rationale, then some updates on interactions with the FDA, and hopefully a discussion on partnering and an update on that. But as you know, this type of update typically happens only when the deal is executed, which always takes a few months following a particular event. So that’s what you should expect from that perspective. Now, on the RMS study, maybe AJ, you want to say a few words about that?

Sure. Excuse me, sure. As you’re thinking, 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 and we’ve actively assessed the right type of RMS study design, and that is something we are contemplating fairly actively right now.

And then regarding the EBV possible opportunity for additional treatment, Jakob?

Yeah, absolutely. So, Salim, thank you for raising this issue of long COVID and the potential role of EBV here. So we’ve been following this story with a lot of interest as well, and as we know, with the pandemic, up to 30% to 70% of COVID patients will suffer from long COVID, so this is becoming a serious emerging health issue in the population. There have been some really high-profile publications of late, and Salim, as you mentioned, there’s the cell publication in January of this year by Sue and colleagues, and it was really interesting; they looked at 309 patients and looked 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 and fatigue, which are not unlike some of the things that you see in MS, where again EBV is the driver. Then there was another publication of note by Gold and colleagues on pathogens that described a small study, where two-thirds of patients with long COVID had EBV reactivation compared to only 10% of control patients. So it looks like long COVID certainly has a risk of developing long COVID with EBV reactivation, and that’s certainly where a product like tab-cel could come in. To further your query, we have been in discussions with leading academic institutions regarding this topic, and this has been going on for several months, so we’re not in a position now to announce any active studies of this sort. But we’re certainly exploring this possibility and think it 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 JPMorgan. You may proceed with your question.

Hey, guys, hope everyone is doing well. Thanks for taking our questions. The first one is on tab-cel, to confirm has the EMA agreed that the pivotal and commercial materials are comparable? And then 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? And then I have a follow-up if I could.

Thank you, Tessa. For the first question, maybe Jakob and I’ll take the second one.

Absolutely. So, thanks for the question, Tessa. And as Pascal has described, we performed extensive studies showing analytical comparability between tab-cel process versions between the pivotal and the intended commercial one. We’ve shared all of this comparability data with EMA through the MA 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. But the preliminary report in that Day 80 critical assessment indicates acceptance of comparability between process versions in that EMA assessment.

To answer your second question, Tessa, there is some natural variability even with a well-controlled and robust manufacturing process for all cell therapies, including other products. We believe that without specific guidance, we have identified the variability range for key attributes based on the extensive and favorable clinical efficacy and safety data we have for tab-cel, which we have presented and published in various forms. We applied established statistical methods to show the compatibility between process versions for each attribute, and we noted minor differences in a few specific areas. We justified these minor differences to the FDA according to ICH guidelines, demonstrating that they do not impact the safety or efficacy clinically and that we have consistent clinical experience across process versions. Therefore, our discussions with the FDA are centered on these aspects. Does that address your questions?

Yeah, that’s really helpful. And just thinking 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 would certainly be nice for us to be able to communicate more than what we love to be able to communicate at the time. What we say is that it’s too early to be very specific about what we will be able to communicate. As we said in the past, we want to preserve the integrity of that study, especially for discussions with the agency, with the FDA. So 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 steps 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. 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 a 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. The second question I have on tab-cel, 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 will answer the first question, which is more about communication, and Jakob, you’ll take the second one, I guess. So on the first question, the intent is indeed, John, to communicate under confidentiality agreements to a selection of potential partners, as well as to the FDA, data from the interim analysis. You’re right to say that even though the main criteria for determining the positional power of the study is going to be the EDSS improvement at six months, because it’s 85% predictive of the ultimate endpoint at 12 months, we will have a number of patients with nine, 12, even up to 18 months, and I think that is important in terms of the overall perspective on the study. Now we will also have access to data on HIE and NPR, as well as some biological markers, and all of that will help us put together a particular package of data to communicate to potential partners and to the FDA with different objectives with these two groups of organizations 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 paths with the FDA.

Yeah, absolutely. So, John, thanks for the question. 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, and that will be very interesting. We’ve also made additional proposals to the agency where we believe that there are other ways to answer the questions the FDA has, rather than embarking on a new clinical trial. We think that we have a range of options. We are in active dialogue with the FDA. Again, we’ll get those official minutes but we’ve also proposed a series of other options to the FDA that we think could resolve this issue.

And more particularly, 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. 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 a range of specifications based on the clinical experience with different values of key attributes. We also have the data that we have started generating by already adding commercial products, including treating patients, which is a great way to generate clinical data. Of course, we are also 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 of the commercial product.

Yes, thank you.

Our next question comes from the line of Phil Nadeau with Cowen and Co. you may proceed with your question.

Hi. This is Ernie Rodriguez for Phil. Thank you for taking our call. First, I would like to clarify if this decision was a change of mind from the FDA or a response to the new analysis.

So in fact, it was, as I said, unexpected. We were surprised by the preliminary recommendation to say that they do not agree with comparability and suggesting a clinical trial with a commercial product. We were very surprised by that because, as you know, throughout the past few quarters, we have regularly, during our quarterly calls, provided a very transparent update of our progress on this aspect of comparability between pivotal and commercial products with the FDA. We’ve explained that initially, we submitted data on key notes for each process version with statistical power with a 95% confidence interval to demonstrate equivalence. Then the FDA said that they wanted to see more, in fact, they wanted to see all the manufacturing batches. We then presented and conducted the CMC Type B meeting in October, with data on all 74 lots that represented the vast majority of total lots produced. The FDA asked for additional questions, and we provided the answers to these additional questions in an IND amendment at the end of the year. Then we had another Type B meeting for the very recent ID meeting, where we put together not only all of these statistical analyses and all of this analytical comparability data, but also putting that in perspective of the clinical data according to ICH guidelines. So 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, and the amount of data that we have to demonstrate comparability is quite impressive in terms of both the analytical data and the correlation linked with the clinical data. It is very consistent in terms of efficacy and safety based on our clinical experience with more than 300 patients treated and more than 180 with EBV+ PTLD, which, I remind you, is an ultra-rare disease. Therefore, it’s quite impressive to see the amount of data that we provided them with. That’s why we were very surprised by their preliminary position.

And how is that decision or the rationale behind that decision different than their agreement to allow you to use the commercial product for the current studies? What’s different there?

It’s a different process. You’re right to highlight it as something interesting, but it is different. When we request the use of a commercial product to treat patients, it follows an IND amendment process. We provided data for an IND amendment, and typically, if they don’t respond within a certain timeframe, we can start treating patients, which we have done, including in single-patient use with patient approval. So, that’s one aspect. Simultaneously, there’s the task of demonstrating comparability for the BLA filing, which involves different questions from the FDA. On one hand, they permitted us to treat patients with a commercial product, which is crucial as we gather data on its efficacy and safety. On the other hand, they have not yet accepted the comparability between the commercial product and the pivotal product at this point.

Okay. And one final quick one, they mentioned they recommended a clinical study. Will they give you any details about what that study may require, and I guess, how confident are you that that decision, that preliminary recommendation can be sorted out?

Yeah, they are proposing to have a dialogue with us on that. But as we said, we have proposed various identities through BLA submission, because we think there are other ways to answer FDA questions, and 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 to establish specification for such a commercial product based on the range of acceptable values of the key attributes, and how these values relate to the accumulating clinical data on the commercial products in the various clinical trials and expanded access programs.

Okay. Thank you. And good luck.

It is an active dialogue, and we look forward for further collaboration with the FDA to find a solution.

Our next question comes from the line of Ben Burnett with Stifel. You may proceed with your question.

Hi, this is Carolina Ibanez 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 events that occurred in the Phase 1 study of ATA2271. Can you share, at this point, the level of cell expansion of therapy in the treated patient who died? And in the context of this fatal event, could you review the rationale behind the use of 1XX co-stimulatory domain over more validated constructs such as CD28? Thank you.

Thank you, Carolina. Jakob, do you want to address these questions?

Yeah, absolutely. So we are communicating with Memorial Sloan Kettering on this particular patient. We will be getting more information on the workup that Memorial is doing for this patient over the course of the coming weeks. So we will have further updates for you in this regard. As we mentioned, the FDA or Memorial Sloan Kettering did their duty and they obviously paused enrollment here. They shared the information with the FDA and with us, and the FDA has supported that decision. Now we are gathering data on things like cytokine profiles and cell expansion and so forth as well, but we’ll be able to provide more detail on this particular patient over the course of the coming weeks.

And related to the 1XX domain, that’s something, as you know, that we’ve been using in this stage in different constructs for our allogeneic CAR T program as well as in the case of 2271, the autologous Mesothelin CAR T. This is a co-stimulatory domain that has already been used in the clinic. This domain has also been licensed to other entities, including Takeda and Fate and others. There are other programs in the clinic, and so far, we’ve not heard about any safety aspect or issue with this program in the clinic. The case of this unfortunate patient with 2271 requires further investigation, because it’s a very complex case with many confounding factors. So we need to conduct that investigation in a thorough manner with our partners at MSK. We will communicate at a proper time when we have a better understanding. It’s a very complex case, many confounding factors, very advanced patients in the fourth line of treatment, and we need to have a better understanding of these different aspects before MSK can make a conclusion, and we can communicate about that conclusion regarding the potential cause of these unfortunate events.

And just one other comment regarding 1XX, we believe that construct, which is really a next-generation co-stimulatory domain, has advantages over CD28, CD3 Zeta or 4-1BB, where the behavior of this co-stimulatory domain leads to better persistence of cells in vivo expansion. Some of the phenotypic aspects of the CAR T cells are favorable relative to the first generation. We think that this particular design from Dr. Michel Sadelain at Memorial Sloan Kettering really does have advantages over first-generation constructs.

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 tab-cel would imply that there would be a difference in safety and efficacy of the product, I assume that would be true. That’s part a, and part b is, it strikes me, though, I guess I’d have to ask how rapidly is the expansion cohort in which the commercial 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. And then 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 sorted out, or just takes longer time? Thanks very much.

Thank you, Tony. Jakob, you take the first question, and I will take the last one.

Absolutely. So thank you, Tony. I would say that we have a lot of clinical experience. Pascal mentioned this, where we've treated over 300 patients through the academic and the Atara program with over 180 patients with EBV+ 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 been true across the various process versions. At ASH, the safety profile is quite excellent. That comes with really outstanding efficacy where once again, if you look at the pivotal ALLELE data at ASH, we see high response rates at 50% 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, and there is great consistency in that clinical data. We believe it’s a very real assuring data set. We also, as mentioned, have submitted this data to EMA and they have preliminarily concluded comparability. So again, 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 very important and we believe it to be quite consistent. In terms of the expansion cohort of patients with the commercial product, we find it very exciting because we did have that IND that has gone through the FDA here in December of last year. We are actively treating patients on expanded access, as Pascal mentioned, also on ALLELE and on the 205 studies. We think that this is reassuring that we’ll be able to provide this data as well, and again, these are types of alternative proposals we are making to the FDA as we continue our negotiations. Again, this is a very active area of discussion.

I want to emphasize, Tony, that in addition to our clinical data with the commercial product, we have gathered substantial clinical information regarding the various values of the key attributes associated with it. It's essential to note that over 300 patients have received treatment with tab-cel. Of those, more than 180 patients have been treated for EBV+ PTLD, showcasing different levels of key attribute values. This experience positions us well, as the commercial product is essentially rooted in that foundation. We already have clinical experience with various potential versions, specifically highlighting the efficacy and safety of key attributes. This gives us strong confidence in identifying a path forward. Concerning your questions about ATA188 and its development impact, it's important to recognize that tab-cel is a unique situation. It has undergone years of development with varying process versions that included some minor modifications. If we maintain the same process version for pivotal and commercial stages, comparability concerns would not arise. Part of our strategy for ATA188 involves ensuring the same process material is used in Phase 3 as in the commercial supply. Additionally, we've gained valuable insights from our interactions with the FDA, enhancing our understanding of how to address potential future inquiries regarding new products. This knowledge, along with our capacity to integrate Phase 3 and commercial supply processes, gives us great confidence that the comparability discussions currently happening with tab-cel, which is indeed a unique case, will not pose an issue for ATA188 or other products in our pipeline. Does that clarify your question, Tony?

Yes, sure, 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.