Atara Biotherapeutics, Inc. (ATRA) on Q4 2021 Results - Earnings Call Transcript
Operator: 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 participant 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.
Eric Hyllengren: 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?
Pascal Touchon: 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 sell 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 the 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 manufacturing process between the pivotal study and intended commercial product to scale up and complied with CGMP, in order to find for regulatory approval from FDA and EMA, we have performed comprehensive studies showing analytical comparability between the pivotal study and commercial manufacturing process versions. These comparability analysis included all 74 available product laws manufactured by Atara and covered 21 key attributes for potency, purity, and alloreactivity. For each key attribute, there is some inherent viability, 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 viability 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 pauses 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 a significant and consistent clinical experience the cost 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 en-a-filing in November 2021. The review and accelerated assessment is progressing as planned following receipt of EMA day 80 critical assessment report, we’ve an anticipated approval in Q4 2022. Pre-launch preparations are progressing well, in collaboration with our partner PSR. In the US, we conducted very recently 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 admission by the end of Q2 2022, as planned. Preliminary meeting responses and discussion did not result in alignment and, unexpectedly, the FDA has initially recommended Atara conducted clinical study with the commercial products, as they 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 have suggested several alternative approaches to progress to a BLA mission, 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 much using our existing inventory of commercial products instead of needing to manufacture new loads 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 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 such credit missionary 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, like food therapy designated product that addresses urgent unmet needs, as patient in second nine BTD 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 in Canada, whether that’s a clinical experience of over 300 patients, including more than 180 with EBV+ PTLD establishes, we believe, very clearly, a safe and effective range of key product attributes values, enabling determination of acceptable commercial product specifications. We are premiers in cell therapy and tab-cel 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 the collaboration with the FDA could allow us to align on a reasonable path to submission and approval, so as to allow us 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 very 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 have adjusted our approach going forward to optimize success with regulatory agencies for other pipeline products and our platform. Turning now to ATA188, allogeneic MS program, momentum continues to build for this potentially game changing product within both the medical and investor community. Recently, two separate non-math 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 patient, 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 these disease as its root cause food 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, 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 the phase two 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 an all 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 to confirm our development strategy going forward. After the IA is conducted, we plan to communicate our decision of next step 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, first, 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 step on the development pathway and potentially other accelerated pathway applications such as EMA D. We will communicate any relevant update as appropriate following these discussions. Additionally, we continue to work on interest from large pharma companies on potential partnering opportunities with at an ATA188 and we will continue this discussion following the IA. Our MS strategy is focused upon ATA188 but it also includes developing an EBV vaccine leveraging a unique knowledge of the link between EBV and autoimmune disease like MS. To this end, we are pleased to announce that preclinical work is progressing at our very own EBV vaccine. For some time, we’ve been collaborating with a vaccine expert QIMA with 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 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 long-term supply agreement with FUJI, which will provide Atara with access to expert cell therapy manufacturing stuff, 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, 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 FUJI going forward. I would like also 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 run way, 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 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 FUJI will be sufficient to fund the company’s planed operation 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. Jakob?
Jakob Dupont: 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 the 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 a baron 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 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 MSA 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 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 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, we will take a look at all these data when making our decision. We have confidence that 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 AI will support determining the sample size necessary to achieve a target conditional power at the end of the study and then we’ll 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’s 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 namely Memorial Sloan Kettering notified the FDA of fatal serious adverse events associated with a patient treated in the ongoing Phase 1. 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 positive 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 falling 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 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 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 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 to turn the call back over to Pascal.
Pascal Touchon: 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 tab-cel in the US. At this time, the FDA’s recommendation is preliminary and we are currently exploring several alternative pathways with FDA to enable the finding of 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. Operator?
Operator: Our first question comes the line of Salim Syed with Mizuho. You may proceed with your question.
Salim Syed: Great. Good afternoon, guys, and thanks for all the color. Two for me, if I can, one ATA188 and one on additional indication that I think you were alluding to in the press release, but just wanted to confirm. So Pascal or Jakob, AJ, one of the bear cases right now on the stock obviously is that the interim analysis is not going to be something that investors can really understand what this data is looking like, because the communication will just be qualitative. So I just wanted to tick through if I could just a few points here. If you’re going to -- if these are at least in the cards of how you’re thinking about communicating this data, so, a, is it possible that you’re going to use some sort of cross trial comparison or reference to the Phase 1 treatment data or some cross trial compared to placebo? B, could can we expect, is it in the cards that a formal partnership is going to come simultaneously with the IA communication? And then, c, is an RRMS trial start something that you’re also considering simultaneously with the IA announcement? And then the second question, is this 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.
Pascal Touchon: Thank you, Salim. So I’ll start on your first question, then Jakob will on the second one. In terms of the IA, what we say that we’ll be communicating of decision related to the study, sample size, and the rationale of that. We have not given any more specifics, in a 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. But we understand the questions from the investor’s community and we’ll make sure that we are as clear as possible to communication at the time of the IA. Now, you asked about from our partnering of current plan and I think that’s what we try to expressed in the prepared remark is that there will be at the time of the IAEA and communication following these interim analyses based on our internal decisions, following access to some specific data, that kind of first line of communication. Then they 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. And as we said, we have a number of very interested parties right now that we 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 be able to work with them on the next steps of development and potential additional 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 being taken about the decision and the rationale, then some update at some stage on interaction with the FDA, and at some stage, hopefully a discussion on partnering and an update on that, but as you know, this type of update is only at the time of the deal is being executive, which always takes a few months following a particular event. So 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?
AJ Joshi: Sure. Excuse me, sure. As you’re, Salim, 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 kind of assessed the right type of RMS study design and that is something we are contemplating fairly actively right now.
Pascal Touchon: And then regarding the EBV possible opportunity for additional treatment, Jakob?
Jakob Dupont: Yeah, absolutely. So, Salim, thank you for raising this issue of long COVID and the role -- potential role of EBV here. So we’ve been following the story with a lot of interest as well and so as we know, with the pandemic, up to 30% to 70% of COVID patients will suffer from long COVID, so this is becoming a really emerging health issue in the population. And 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 looking for various underlying causes for long COVID or PASC. And they actually found that one of the four risk factors for developing PASC was actually reactivation of latent EBV. So -- and 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 in MS, where again EBV is the driver. And then there was another publication of note by Gold and colleagues on pathogens and described in a small study, but two-thirds of patients with long COVID had EBV reactivation, which compared to only 10% of control patients. So it looks like long COVID certainly, there’s a risk there of developing long COVID with EBV reactivation, that’s certainly where a product like tab cell could come in. So 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, so we’re not in the position now to announce any active studies of this sort. But we’re certainly exploring this possibility and think that this could be quite interesting to explore further with academic groups.
Salim Syed: Very helpful. Thanks so much, guys.
Operator: Our next question comes from the line of Tessa Romero with JPMorgan. You may proceed with your question.
Tessa Romero: 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.
Pascal Touchon: Thank you, Tes. First question, maybe Jakob and I’ll take a second one.
Jakob Dupont: 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.
Pascal Touchon: And to your second question, Tes, I think the -- as we mentioned, there is some inherent variability even with the well controlled and robust manufacturing process for all cell therapies, including . And we are confident that in the absence of specific guidance, we have determined the range of viability for the values of key attributes based on these extensive and favorable clinical efficacy and safety data that we have available for tab-cel and that we’ve presented and published across different forms. Now, what we’ve done is that we’ve applied specific and well-established statistical methodology to demonstrate the compatibility between positive versions for each attributes and there have been minor differences on the few specific attributes. And what we did with the NDMA, that we justified this 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 and we had consistent clinical experience across process version. So discussion with the FDA is really related to these aspects. Does it answer your questions?
Tessa Romero: Yeah, that’s really helpful. And 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?
Pascal Touchon: That would certainly be nice to us to be able to communicate more than what we love to be able to communicate at the time. What we say 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. So at this stage, we cannot give any more specific 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.
Tessa Romero: Okay, got it. Thanks so much, guys.
Pascal Touchon: Thank you, Tessa.
Operator: Our next question comes from line of John Newman with Canaccord. You may proceed with your question.
John Newman : 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 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 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.
Pascal Touchon: 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 selection of potential partners, as well as to the FDA data from the interim analysis. And 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 a 12 months, we will have a number of patients with 9, 12, even up to 18 or whatever month and I think that is something that will be important in terms of the overall perspective on the study. Now we will also has access to data on HIE and NPR as well as some biologics markers, and 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 these two different groups 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 paths with the FDA.
Jakob Dupont: Yeah, absolutely. So, John, thanks for the question. So 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 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 that the FDA have, rather than embarking upon a new clinical trial. So 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.
Pascal Touchon: And 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, establish a safe and effective acceptable range of values for each attributes. So we have ways to establish the specification of a commercial product that will support a safe and effective product. And 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 adding commercial products including treating patients, which is a great way to generate clinical data. And 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 of the commercial product. Does it answer your question?
John Newman : Yes, thank you.
Operator: Our next question comes from the line of Phil Nadeau with Cowen and Co. you may proceed with your question.
Ernie Rodriguez: Hi. This is Ernie Rodriguez for Phil. Thank you for taking our call or our question. I guess first I have a clarification, did this decision -- was that a change in mind from the FDA or was it a reaction to the new analysis?
Pascal Touchon: So in fact, it was, as I said, unexpected. We were surprised by 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 few quarters we have given regularly during our quarterly call a very transplant update of our progress on this aspect of comparability between pivotal and commercial product with the FDA. We’ve explained that initially, we are submitted data on key notes for each portion version with 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. So we then we presented and we are the CMC Type B meeting in October, with data on all 74 rolls that represented the vast majority of the total loss produced. And then the FDA asked for additional questions, we provided the answer to these additional questions in an IND amendment at the end of the year. And then we had another Type B bushing book for the very recent ID meeting, where here we put together not only all these statistical analyses, not only all these 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 provided 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 and linked with the clinical data and very consistent clinical data in terms of efficacy and safety, the cause versus reaction because more than 300 patients treated and more than 180 with EBV+ PTLD, which I remind you is an ultra-rare disease. So 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.
Ernie Rodriguez: 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, because you’re treating patients with that commercial product? What’s different there?
Pascal Touchon: 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 you -- when we ask them to be able to use a commercial product to treat patients that has been through an IND amendments. So we provide them data for an IND amendment and as usual, when they view the data, if they don’t react within a certain period of time, you can start to treat patients and we started to treat patients, including in single patients use that they approved patient or patients. So that has been one process, and in parallel there is this process of demonstrating comparability for the BLA filing, which is, of course, a different process, I think, different type of questions from the FDA. So, on one hand, they allowed us to be able to treat patient with a commercial product and 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.
Ernie Rodriguez: 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 ?
Pascal Touchon: Yeah, no, they are proposing to have a dialogue with us on that. But as we said, we have proposed identity stuff through BLA submission, because we think that 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 do you establish specification for such a commercial product based on the range of acceptable values of the key attributes, as well as these new clinical data that we are accumulating on the commercial products in the various clinical trials and expanded access program?
Ernie Rodriguez: Okay. Thank you. And good luck.
Pascal Touchon: It is an active dialogue, and we look forward for further collaboration with the FDA to find a solution.
Ernie Rodriguez: Thank you.
Operator: Our next question comes from the line of Ben Burnett with Stifel. You may proceed with your question.
Carolina Ibanez: 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 of a more validated constructs such as CD28. Thank you.
Pascal Touchon: Thank you, Carolina. Jakob, do you want to address these questions?
Jakob Dupont: Yeah, absolutely. So 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. So we will have further updates for you in this regard. As we mentioned, FDA or the Sloan Kettering did their duty and they obviously they put a temporary hold on enrollment here and then they shared the information with the FDA and with us and the FDA has supported that decision there. Now we are getting data in 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.
Pascal Touchon: And related to the 1XX domain, that’s something, as you know, that we’ve been using in this stage in different contracts for allogeneic CAR T program as well as in the case of 2271, the autologous Mesothelin CAR T. And this is a co-stimulatory 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 programming 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. So we need to do that in a very good way and deep way with our partners at MSK. And we will communicate in proper time when we have a better understanding. It’s a very complex case, a lot of confounding factors, very advanced patients in 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 about the potential cause of these particular unfortunate events.
Jakob Dupont: And just one other comment regarding 1XX, we do believe that that construct which is really a next generation co-stimulatory domain has advantages over CD28, CD3 Zeta or 4-1BB per se, where the behavior of this co-stem to more domain in terms of persistence of cells in vivo expansion. Some of the phenotypic aspects of the CAR T cells are really favorable relative to the first generation. So we think that this particular design from Dr. Michel Sadelain at Memorial Sloan Kettering really does have some advantages over the first generation constructs.
Carolina Ibanez: Understood. Yes, perfect. Thank you again.
Jakob Dupont: Thank you.
Operator: Our last question comes from the line of Tony Butler with ROTH Capital, you may proceed with your question.
Tony Butler: Thanks very much, Pascal. The notion of the FDA not agreeing with comparability on tab-cel would didn’t 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 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 light in the newer product that 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. And then question two is what gives you confidence that 188, for example, would not be affected in any way, either as this progresses and/or get solved or just comes to a standstill, or just takes longer time? Thanks very much.
Pascal Touchon: Thank you, Tony. Jakob, you take the first question. I will take the last one.
Jakob Dupont: Absolutely. So thank you, Tony. I will say that we now have a lot of clinical experience. Pascal mentioned this, where we treated over 300 patients through the academic and the Atara program 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. And this has really been true across the various process versions. And as you saw at ASH, the safety profile is really quite good. And 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% 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. And so we know what the specifications are for the various process versions there and there is great consistency in that clinical data. So we believe it’s a very real assuring data set. We also, as mentioned, have submitted this data to EMA as well and they have preliminarily come to the conclusion of 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 really important and we believe it’s quite consistent as well. And so in terms of, you mentioned, this expansion of the cohort of patients with the commercial product, we think it’s very exciting one 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 studies. So we think that this is reassuring that we’ll be able to provide this data as well. And again, 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.
Pascal Touchon: And I add Tony that on top of having accumulating now clinical data with the commercial product, we had already significant clinical data with the different values of the key attributes that are part of the commercial products. That’s something that is important to have in mind that among the 300 patients have been -- more than 300 patients have introduced to tab-cel. Among the 180 plus patients have been treated with tab-cel for EBV+ PTLD, there have been different level of values for key attributes. So we have that trench and the commercial product is within that trench. So we have clinical experience already with different possible versions, but of the specific value of key attributes that shows efficacy and safety. That’s what makes us extremely confident that we find a way forward. Now, your questions on ATA188 is and why do we think there is no particular impact on these development? First of all, tab-cel, again, is very special case, it has 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 are 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 material used in Phase 3 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 new product. So I think this learning and this ability to have Phase 3 and commercial supply makes us also extremely confident that this particular debate on comparability we’re having right now on tab-cel, 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?
Tony Butler: Yes, sure, Pascal. Thanks very much. Thank you, Jakob.
Pascal Touchon: Thank you.
Operator: 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.
