Good day, ladies and gentlemen, and welcome to Atara Biotherapeutics Quarter Three 2021 Financial Results Conference Call. All lines have been placed on a listen-only mode, and the floor will be open for questions and comments following the presentation. If you should require assistance throughout the conference, please press star zero on your telephone keypad to reach a live operator. At this time, it is my pleasure to turn the floor over to your host, Eric Hyllengren, VP, Investor Relations and Finance. Sir, the floor is yours.
Thank you, operator. Good morning, everyone, and welcome to Atara's third quarter 2021 results conference call. Earlier today, we issued a press release announcing our third quarter 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 morning. We continue to make meaningful progress across our three strategic priorities, tab-cel, ATA188 in multiple sclerosis, and our next-generation allogeneic CAR-T programs. Today, we announce for the first time positive top-line data from our pivotal phase III ALLELE study for tab-cel in EBV+ PTLD, which includes new analysis, additional patients, and extended follow up. These data confirm a strong objective response rate of 50%, with clear durability of response and overall survival of 89% at 1 year in responders, while still demonstrating a well-tolerated safety profile in line with prior results. These data will be the basis for the imminent MAA submission in the E.U. and our planned BLA submission in the U.S. next year for patients with EBV+ PTLD.
We are very excited to submit our filing in the next few days for approval in Europe. With our recently granted accelerated assessment, we anticipate a decision regarding EU Tab-cel approval in the second half of 2022. Additionally, in October, we were extremely pleased to announce our exclusive commercialization agreement with Pierre Fabre for tab-cel in Europe, Middle East, Africa, and other select emerging markets for EBV-positive cancers. We believe this partnership reinforces the commercial opportunity for tab-cel in these markets and maximizes the strategic and financial value of this potentially transformative therapy. On the U.S. regulatory front for tab-cel, we continue to make stepwise progress through Type B meetings with the FDA. In particular, we have aligned with the FDA on comparability approach, including the statistical methodology.
Based on new requests from the CMC review team following our recent interactions, we will provide the agency additional analysis of CMC data we have already submitted. We plan to have further interactions with the FDA in Q1 2022 to resolve the outstanding items and expect to complete the BLA submission for tab-cel in Q2 2022. Concurrently, we continue to work on pursuing the development of tab-cel in additional EBV patient populations with a primary focus on immunodeficiency-associated lymphoproliferative disorders, IA-LPDs. Enrollment is continuing at sites in the label expansion multi-cohort study, which is evaluating six patient populations, including four within IA-LPDs and two in other EBV-driven disease in the U.S. and EU. The multi-cohort study data is expected in 2023, and we believe this could be a meaningful label extension opportunity.
Turning to ATA188, our potentially transformative therapy for patients with progressive multiple sclerosis. Last month, we presented at ECTRIMS updated phase I open-label extension, or OLE, data in patients with progressive MS treated with ATA188 for up to 39 months. As a reminder, the natural history of patients with progressive MS is continuous disability progression. The OLE data we presented demonstrate that patients have achieved sustained disability improvement, or SDI, at a higher rate and longer duration than would be expected based on this natural history. The majority of SDI seen in the data presented is driven by sustained EDSS improvement, which is our primary endpoint in our phase II randomized controlled EMBOLD study. Additionally, we presented magnetization transfer ratio, MTR, data, an imaging biomarker considered to reflect the state of myelination in the central nervous system.
The statistically significant increase in MTR parallels the EDSS improvement observed and provides evidence that remyelination may be the driver for clinical improvement. This potential biological basis for clinically significant EDSS improvement observed with ATA188 continues to build awareness and interest in the transformative potential of ATA188 in the medical community and with potential partners. As a reminder, in the first half of 2022, we will conduct an interim analysis, or IA, to assess efficacy and safety. We plan to disclose our decision regarding the next steps for the program and our rationale for this decision based on data from the IA while still maintaining the integrity of the study. We believe this IA will be an important milestone for the company, investors, and potential strategic partners.
With regard to our CAR-T portfolio, our mesothelin product candidates, ATA 2271 and ATA 3271, partnered with Bayer, are progressing well. Our collaborators at Memorial Sloan Kettering will present pre-clinical, clinical, and translational data from the lowest dose cohorts of the open-label single-arm phase I clinical study of ATA 2271, an autologous CAR-T therapy targeting mesothelin, through a mini oral presentation at ESMO IO in December 2021. Meanwhile, we continue to make progress on IND-enabling studies for ATA 3271, an off-the-shelf allogeneic CAR-T therapy targeting mesothelin using next-generation PD-1 dominant negative receptor and 1XX CAR co-stimulatory signaling domain technologies, for which we anticipate an IND filing in the second half of 2022. Additionally, we plan to present new pre-clinical data confirming potential benefits in solid tumors for ATA 3271 at SITC in November.
Turning to ATA3219, our allogeneic CD19-targeted CAR-T for patients with B-cell malignancies. We expect to submit an IND in Q1 2022. ATA3219 leverages our next-generation 1XX CAR co-stimulatory signaling domain and allogeneic EBV T-cell platform, and is a potential best-in-class therapy that does not require TCR or HLA gene editing, which we believe is a key differentiator of our platform. To further support our differentiated allogeneic CAR-T platform, we have invested in new capabilities to support our product pipeline and further drive innovation by opening our new Atara Research Center, or ARC, in Thousand Oaks, to house our translational and preclinical science, process science, and analytical development teams. Our talented team at this new facility will support our product pipeline and further drive innovation by leveraging our unique and differentiated allogeneic cell therapy platform. Moving now to our financials.
With regard to our cash position and runway, we ended the third quarter of 2021 with $357 million in cash. This includes $46 million for the sales of shares of common stock through our ATM facility. We believe we are sufficiently funded into the second quarter of 2023 with this cash and the $45 million upon payment received in the Pierre Fabre commercialization agreement. As we head into the final months of 2021, I'm proud of the Atara staff and partners for steady progress in improving the lives of patients with serious disease. We are very close to filing the MAA in the EU for tab-cel, the first ever application for an allogeneic T-cell therapy in the world. Our progress in ATA188 clinical study could bring a truly transformational therapy to MS patients.
We look forward to providing more updates to you in the coming weeks. I will now turn the call over to Jakob. Jakob?
Thank you, Pascal. I'd like to provide further color on the progress we made during the third quarter in advancing our three strategic priorities. As Pascal mentioned, today, we announced the first presentation of new positive data from the pivotal tab-cel phase III ALLELE study in EBV+ PTLD, confirming a strong objective response rate, or ORR, durability of response and continued well-tolerated safety profile, which support the imminent European MAA submission and planned BLA submission. These data will be presented at an oral session at the American Society of Hematology annual meeting next month. In these data, we observe a 50% ORR as measured by independent oncologic response adjudication, with a response of 50% at both PTLD following SOT and PTLD following HCT. This response includes both complete and partial responses.
Importantly, overall median time to response was 1.1 months, which is critical in this setting where patients are in urgent need of treatment as they only have a few months to live. Of 19 responders at this point in time, 11 have duration of response lasting more than six months, with a median duration of response not yet reached. The one-year survival rate was 61% overall, 57% for SOT, 67% for HCT. Those who responded had a longer survival compared to non-responders with a median OS not reached and one-year survival rate of 89% compared to 32% in non-responders. Safety findings were consistent with previously published data, with no reports of tumor flare reaction and no confirmed evidence of graft versus host disease related to tab-cel treatment.
Next month at ASH, we will present additional data on tab-cel through several abstracts, including a second oral presentation on long-term survival from phase II and multi-center EAP studies in relapsed refractory EBV-positive PTLD, showing median overall survival of 54 months and OS at 2 years, reaching over 86% in responders where patients experience CR or PR. As a reminder, both pivotal data from the ALLELE study and historical data will be included in the regulatory filings of tab-cel. We believe that tab-cel is a truly transformational therapy for these patients with EBV-positive PTLD, where the median survival is just a few months for patients who have progressed on one prior line of therapy. The data we have shown today serves to deepen our conviction around the potential benefit that tab-cel can bring to patients.
Regarding the tab-cel regulatory discussions in the U.S., as Pascal mentioned, we continue to make good progress with the FDA. We held a Type B meeting with the FDA CMC review team in October, and we achieved agreement on comparability approach, including the statistical design, to assess comparability between pivotal and commercial tab-cel products. Importantly, the FDA has not requested additional new studies or manufacturing lots. We are planning to submit additional analyses on data already submitted to the FDA at their request. We plan to interact with the FDA in the first quarter of 2022 regarding these analyses to gain agreement on comparability from pivotal to commercial tab-cel. We've also shared the clinical data from the pivotal ALLELE phase III study along with data from supportive and historical studies. We received productive feedback from the agency that will help to guide the structure of our BLA filing.
Following agreements on comparability, we plan to have a pre-BLA meeting prior to submitting the BLA for tab-cel in the EBV-positive PTLD in the second quarter of 2022. Moving to ATA188, our product candidate for multiple sclerosis. At ECTRIMS last month, we presented encouraging 2-year clinical data from the phase I open label extension and new translational MTR data from the phase I study of ATA188 in progressive MS. As context, patients who have progressive MS will unfortunately only continue to worsen over time as the disease progresses. If there was a treatment that offered the possibility of maintaining their current level of physical function, it would have a tremendous impact on these patients' lives. As we saw in the clinical data presented at ECTRIMS, most patients in the OLE were progression-free.
Taking it a step further, the prospect of a treatment improving a patient's disability would be even more transformational for them and has never been seen before. The data we presented at ECTRIMS showed that seven of eight patients with sustained disability improvement or SDI in the phase I or open label extension, SDI was maintained at all subsequent time points up to 33 months, with multiple patients regaining enough function that they no longer needed a walking aid and were able to walk a few hundred meters unassisted. With regard to presentation of new MTR data, there's an increasing body of scientific evidence using MTR as a key measure of remyelination in MS.
In patients treated with ATA188 who achieved sustained EDSS improvement versus those who did not, MTR for non-enhancing T2 chronic brain lesions increased, with a trend at 6 months that achieves statistical significance at 12 months. This significant MTR increase may be indicative of remyelination. A similar trend of MTR increase has also been seen in normal-appearing brain tissue. The ATA188 phase I MTR data assessing normal-appearing brain tissue in PPMS and SPMS patients compares favorably to siponimod data from their phase III study in SPMS. This comparison is made on slide 37 of our updated corporate presentation, for which I'd like to highlight the following. The expected course of MTR in progressive MS is decline or demyelination. As seen in the placebo group from the phase III siponimod study data, siponimod showed slowing of demyelination based on the small decrease in MTR versus placebo.
On the other hand, ATA188 uniquely indicates remyelination based on a relatively large magnitude increase in MTR. On slide 38, starting at 6 months after ATA188 treatment in normal-appearing brain tissue and unenhancing T2 lesions, MTR is increased in patients with EDSS improvement and relatively stable in those without. This parallels the time course of clinical EDSS improvement. For the first time in progressive MS, ATA188-treated patients with EDSS improvement demonstrated a statistically significant increase in MTR in unenhancing T2 lesions in patients with EDSS improvement. This MTR analysis, where the time course for increased MTR parallels the EDSS improvement of the observed, provides evidence that remyelination may be the driver for clinical improvement and supports a potential biological basis for the clinical EDSS improvements observed with ATA188.
Moreover, these unique MTR findings suggesting remyelination has generated new investigator inquiries and excitement as we continue to enroll the phase II randomized placebo-controlled EMBOLD study. We believe this MTR data further support the probability of success of ATA188 as we head towards the upcoming interim analysis in the first half of 2022. Turning to our potentially best-in-class CAR-T portfolio. As a reminder, our approach does not require TCR or HLA gene editing and presents a differentiated approach that that retains the endogenous T-cell receptor. This has been shown in academic studies to increase persistence, durability, and trafficking. The safety and tolerability of our allogeneic EBV T-cell therapies and platform has now been supported by clinical studies of, and evidence in approximately 400 patients in various disease areas. Our EBV platform enables scaling of manufacturing in stirred-tank bioreactors.
In closing, I would like to extend my gratitude to the Atara staff, our collaborators, and the patients involved in our studies. Working together, we're hopeful that we will bring our transformative therapies to patients in need. I will now turn the call back to the operator to begin the QA portion of the call. Operator?
Thank you. The floor is now open for questions. If you do have a question, you may press star one on your telephone keypad at this time. If your question has been answered, you can remove yourself from the queue by pressing one. Again, ladies and gentlemen, it's star one to ask a question. Our first question comes from Salim Syed from Mizuho. Go ahead.
Yeah. Hi. Thanks, guys, for all the color and congrats on the progress. A couple from me on ATA188. Pascal, Jakob, when we get the data in the first half of 2022, you know, historically in multiple sclerosis trials, I think folks generally understand companies need two trials to file for regulatory approval. Progressive multiple sclerosis, there's also an unmet need. I think it's pretty established that you guys will let us know if you're gonna have a large increase in N here or a smaller increase.
I'm just wondering, is a fair way to interpret this is that if you say, "Hey, you know, we're going to increase this by a large N," that the P value you're seeing is less than 0.01 and you only need one trial, and if it's a smaller increase, the P value is something like, you know, you can, you think you can get to a 0.05 or less? Just wondering if you can actually give us that P value when you disclose the data. The second question, just more around the limited disclosure that we're gonna get in the first half of 2022. Can you just remind us, is this being driven by the FDA, where they've asked you to limit the disclosure, or is this more an Atara decision?
The reason why I ask is I think some investors would argue here that it's more capital efficient to disclose more data. I'm just sort of curious how conceptually you're thinking about that. Thank you.
Oh, thank you, Salim, for your question. I'll ask AJ to start answering there and starting with the second question because it will give color to the first one there. AJ?
Sure. Thanks for the question, Salim. Oh yeah, starting with the second question, maybe we can just give an overall kind of view on this. As you know, the IA for this randomized placebo-controlled phase II study. We're gonna hit both efficacy and safety criteria as well as some additional biomarkers. As you know, when we do the IA, we'll have a range of results, everything from people who've been in the study for well beyond a year, all the way to people who have data around the 3-month timeframe. It's gonna be a fairly large data set for us there. The objective, as you kind of alluded to, is to adapt the sample size, which at this stage is 80.
You know, the plan is to potentially adapt it to a larger size depending on the trend we see and possibly discussions with the FDA. What we're saying is we are in an appropriate form, we will communicate publicly after that IA is done, both what we plan to do in terms of the adjustments in sample size, as well as provide detail on the rationale that we're using based on those IA results. We are gonna provide some additional detailed rationale there. Now, today we won't get into the specifics of, you know, the actual data that we're going to share, because to some extent, the actual data that we'd share would depend on the IA results.
We can emphasize that the IA-based rationale for any adjustments we're gonna make in both studies will be made clear, but we still have to maintain the blinding integrity of that double-blind study. That kind of leads into that last question that you were asking. Maybe I can just give an example to add a little color to this as to what we'll provide and what we won't be able to provide. At the time of the IA, let's say we see a trend of EDSS improvement that in the active ATA188 arm, that's similar to what we observed in the phase IA study. Then we see a trend for placebo that's pretty much what we expected in our modeling.
At that point, we'd likely either decide to make no or minimal change to the sample size, except if we believe that once we have a discussion with the FDA, that we could transform the study into phase III, which would be, of course, a much larger expansion. At that point, then we'd publicly disclose our decision. We'd give the specific rationale around it without disclosing the detailed data so we can preserve the integrity of the study. This is really again, it's really about this as a strong, robust phase II. It's still fully placebo-controlled. Not like an oncology setting where you. In MS, we're gonna have to do as much as we can to maintain the integrity of that study.
That's the main rationale behind giving details on the rationale, but not details on the data itself. You know, that kind of leads into your second question about will we be disclosing P values. We're not gonna be discussing specific P values or the statistical methodology at this point for the study. We wouldn't be disclosing that at the IA.
Got it.
Again, Salim, the aspects related to the specifics, we cannot give you the specifics at that time or the actual information we share, because that specifics will be depending on the results and our discussion with the FDA. We do plan to communicate enough to make sure that there is clear understanding from investor community in particular about how meaningful is this particular milestone of this interim analysis there.
Super helpful. Thanks so much, guys. Congrats on the progress.
Our next question comes from Matt Phipps from William Blair. Go ahead, Matt.
Hi, everyone. Thanks for taking my question. Just wanted to try to clarify some of the regulatory discussions around CMC. So, any color on what the CMC team is focused on this point? 'Cause you said on the Q2 call that you were aligned regarding comparability approach. Just kind of curious what additional information you're looking for. Again, just to make sure I understand the sequence of events correctly, you're gonna submit this additional analysis that the FDA requested and then discuss that in Q1. Will that be another Type B meeting or something informal, and then hold a pre-BLA meeting in Q2?
Thank you, Matt. Maybe I'll start, and Jakob can chime in if needed there. As you said, we have reached agreement on the methodology. We've presented during the recent Type B in October, this new comparability analysis. You may remember we said in Q2, this is a new analysis based on analyzing all the batch manufactured by Atara, you know, these 74 batches there. So that's a lot of data that we sent to the FDA there. We believe and we've shown in our analysis that this set of data demonstrate comparability between the pivotal study process and the intended commercial process version there. Keeping in mind, of course, as you may remember, that in reality, these process differences between these manufacturing process version are minimal. You know, they're really minimal there.
We analyze all the batches, presented all this data, an immense amount of data to the FDA. What the FDA has asked is additional data analysis related to a few attributes there, and we will provide them because the data, they have the data already, but they ask us to do additional analysis. We'll do this additional analysis. We'll provide the FDA with this analysis for this data already submitted. Once they have the analysis, we plan for further discussion. We are not commenting yet on the type of discussion, but a Type B would make sense for sure there.
Then once we've got to that level of discussion and alignment with the FDA and agreement on comparability, that's where then we will go to a pre-BLA meeting to be able then to present all what we plan to submit, including clinical and all the other stuff. We'll be able to file for BLA. That's the sequence of events there that we are planning based on the discussion with the FDA. Does it answer your question?
Yeah. No, thanks. Thanks, Pascal. It's helpful. Maybe on the kind of ASH data we'll see in just the ALLELE study. Maybe you can just. I don't know if you can say this yet, but maybe how many patients received like a switch in cell line, and if that, you know, was included in the kind of these response rates. Could you remind me on that?
Yes. Jakob, do you want to answer that one?
Yeah. Matt, thanks for the question. We haven't included that particular detail in the abstract at this point in time. What you can see here, and this is what we're reporting obviously, is that we have a 50% response rate in all these PTLD patients and a 50% response rate in both HCT and SOT. This is of course by independent oncologic and radiographic assessments. This is really independently reviewed. I will say that most of the responses were with the first therapy. Of course we can switch lots. Those details were not included in the current abstract presentation.
You can expect it's an oral presentation at ASH, so you can expect much more detail at ASH.
Great. Thank you.
Our next question comes from John Newman from Canaccord. Go ahead, John.
Hi, guys. Good morning. Thanks for taking my question and congrats on all the progress, especially in Europe with tab-cel. The question I have, excuse me, in the past, FDA has tended to look at durability at six months for CAR-T products or T-cell products. In your case, I think you provided some additional durability data to the FDA. I just wanted to ask, my understanding is that the median follow up for this study at this point is very, very long. The reason I'm asking that is because I'm assuming that at this point, the FDA may have all the data that they would want regarding the durability. I just wondered if you could perhaps just comment a bit about the follow up for the study. Thanks.
No, thank you, John, for your question there. Jakob, do you want to take that one?
Yeah, sure. Absolutely. Thanks, John. As you recall, last year we disclosed that the data cut that we provided the agency with the number of patients, and this is in October of last year, was a reasonable number from the FDA perspective, but they wanted this six months duration of response data, which again is required for regulatory approval, which is why we did this most recent data cut. We do, again, have this durability of response data, as I mentioned earlier in my comments, that we think are quite encouraging. I think the 89% survival of responders at one year is quite encouraging. That's for the ALLELE study. Now, I also mentioned that we have a second oral presentation at ASH, which is on our historical and supportive studies.
There again, we have a median of 56 months of overall survival in that circumstance, which again is of course a very profound result for these patients. I think the totality of the data between the ALLELE study and then the additional supportive data that will also be presented at ASH, again, shows a long-term benefit for these patients where you get high response rates, a rapid response, a durable response, and an impact on overall survival for these patients that have a really lethal disease.
Okay, great. I had one additional question, sort of a general question on ATA188. Just wondering if you could comment on the understanding that you have regarding the way the agency thinks about the potential for EDSS improvement versus simply slowing EDSS decline. I think the MS therapies that have been approved for progressive MS are simply slowing the decline. I'm just curious if you could perhaps provide some color on how the agency thinks about something like EDSS improvement.
Thank you, John, for your question. I'll start and AJ or Jakob, you might want to chime in. I mean, that's why it was so important for us to have this dialogue with the FDA at the end of last year, where we align on these primary criteria of EDSS sustained improvement at 12 months, which is having 2 consecutive time points for improvement and the last one being at 12 months there. That was very important because as you say, it was not yet. No product has been approved. To our knowledge, only one has tried to develop on the EDSS improvement for the phase III. That was a MedDay study there with unfortunately that study failing there. It was very important there that we talk with the FDA and we align with them.
They did say that sustained disability improvement is an important primary endpoint for progressive MS, and they prefer to have EDSS improvement. That's why we changed our primary criteria in the EMBOLD study to be sustained EDSS improvement. That's a first. Nobody else has done that. Nobody else is trying to do that, because even the few studies that are trying to go now in PMS, nobody's trying to look at this sustained EDSS improvement. That's a first that has been aligned with the FDA. Does it answer your question, John?
Yes. Thank you.
Our next question comes from Tessa Romero from JP Morgan. Go ahead.
Hey, guys. Good morning. A couple of questions from me this morning on the CAR-T programs, if I could. Just thinking a little bit about the mesothelin CAR-T program, ATA2271, ahead of the updates coming up here at ESMO IO in December. What are you looking to understand in this data update, given what we know from the prior MSK data and also your allogeneic program? What would be a win scenario, in your view here? Then my second question is on the ATA3271 allogeneic program. What are the gating factors to IND submission at this point? Thanks so much.
Thank you very much for your question. Jakob, do you want to take the first one?
Yeah, absolutely. Tessa, thanks for your question. As mentioned, we're excited to announce that we have a mini oral presentation with our collaborators at Memorial Sloan Kettering for the autologous mesothelin program. Again, we think that our Allo CAR-T platform really is an exciting one and potentially best in class because we are leveraging technology like 1XX next generation co-stimulatory domain and PD-1 dominant negative receptor. Of course, this first study is for the auto program, and then we have the following allogeneic one using our EBV T-cell platform. Again, we don't do gene editing, and we think that that's really important for the performance of the cells and to limit risk as well.
At ESMO IO, our collaborators at Memorial Sloan Kettering will present preclinical data for the program, but also clinical data from low-dose patients. You'll see safety there, translational data, as well as some potential early efficacy. I will say, of course, these are low-dose cohorts, but again, I would say safety is really important here, of course, as we move into these CAR-T therapies for solid tumors. I also think, you know, these questions of persistence of the cells is really important. Turning to the allogeneic program 3271. Just one comment. We are having a presentation here at SITC very shortly with preclinical data, updated data for that allogeneic mesothelioma program. That will be a poster presented at SITC.
Then we're very much on track with the IND filing in the second half of next year. I will say, you know, as with any IND, you have to get all of your studies, your ready for the IND filing, including of course, for this type of therapy, the manufacturing aspects for this type of program. I will say everything is moving ahead very well with our partner, Bayer here. And again, preceding that will be the IND filing for 3219, which is our allogeneic CD19 CAR-T, which we think could be best in class. We're targeting a Q1 IND of next year.
Tessa, maybe two additional points. We are very excited about this program, ATA3271 in particular. One aspect that is very unique to Atara. In fact, two aspects. First one is this ATA3271 is going to be made, is being made right now in stirred-tank bioreactor. That's a big first for an allogeneic CAR-T or CAR-T in general there. I think that's why it's taking the time to put that together, because that's a big first. We have already evidence at some early stage that we can make this allogeneic CAR-T into stirred-tank bioreactor, which, we believe, is going to change radically the manufacturing efficiency of allogeneic cell therapy manufacturing. Watch the pace there. The other aspect is the fact that we are maintaining TCR in ATA3271.
We're maintaining the EBV TCR there in our manufacturing process. We believe that's very important, not only from a safety point of view, as recent examples have been shown, but also we believe from an efficacy point of view. In fact, recently a clinical study has been published in Nature using mesothelioma CAR-T cells that were edited to lose TCR and PD-1 expression. What was very interesting in this phase I study that the authors could not detect CAR-T cells in 12 of the 15 patients. The only three patients in which they could detect were the patients for which they were, in fact, having a few of TCR that were not gene edited, and they were the TCR-positive CAR-T cells that were present there.
For us, it's a clear evidence that if you maintain the TCR, you are more persistent. If you delete the TCR or you modify the TCR, the endogenous one for allogeneic CAR-Ts through gene editing, not only you create risk in terms of having additional gene addition in terms of safety, but you also limit the persistence of these cells that will stay only for a few weeks. Does it answer your question?
Absolutely. Thanks so much for the color, Pascal and team. Really appreciate it.
Our next question comes from Phil Nadeau from Cowen and Company. Go ahead, Phil.
Hi, good morning. Let me add my congratulations on the ALLELE data. A few questions from us on tab-cel. Just first on the guidance for Q2 FDA filing, I'm curious how confident are you that you can complete the BLA in Q2? It does seem like the FDA and the CMC division in particular in dealing with cell therapies is kind of evolving its requirements on the fly. Appreciating that you have alignment, how confident are you that you know exactly what the FDA wants and that there's not gonna be a newer request when you talk to the agency in Q1?
No, thank you, Phil. I'll start, and Jakob will chime in. I mean, first of all, I'd say we're very confident that we are ready to file. I mean, as I said, we are filing in the next few days in Europe, so we have a full file ready to go. On all aspects of this product, we believe we have invested and developed a product that is of high quality and with great data there, and we're going to file in Europe in the next few days. Now, in terms of the U.S. and the FDA discussion, I mean, it's true that it's a stepwise type of process so far with a lot of questions coming there. There is a lot of data also that we put to them.
I mean, we are discussing things that very often are more at the BLA review level, and we're doing that in validation study meetings that we are doing with the CMC review team. We are making progress, stepwise progress there. We certainly are understanding their questions, and we're going to put together this new analysis they're asking for and have other interactions with them. We cannot predict whether they will have other questions, but we think we have given them all the data that exists on the product. It's really around new analysis more than trying to create new data at this stage. Jakob, anything to add?
Yeah. Just to maybe amplify that as well, I do think as you see, we're making this stepwise progress. At the last quarterly call, we announced that we've got this clarity and agreement that the FDA wanted to see all of the lots that were manufactured in order to make this determination of comparability between pivotal and commercial material. The great news is we can do that. We have all those lots. That was great clarity to get from the agency. At this quarterly call, we can now announce that we've made further stepwise progress with that October Type B meeting, where we've now come to agreement with the FDA on comparability approach, including the statistical methodology. Again, this was an area of much discussion, and we came to agreement there.
Then the agency have now further focused us and said that they want additional analyses on certain data points here, which we're now providing to them in advance of our next interaction with the agency in Q1 of next year. Again, I think there is clear evidence of progress here, and I think we are confident in that progress. As Pascal says, it's really incredible, you know, as a pretty small company here that that we're completing our first regulatory filing and submitting in Europe here, as Pascal mentioned, within the next couple of days. The implications of that is that we have a full regulatory filing that's been completed, and we can leverage all of those documents, all of those analyses and all of that data in the BLA filing. We're really ready to go.
We've also, of course, shared clinical data with the FDA from the ALLELE study and the other supportive studies as well, and gotten guidance from the FDA in that clinical feedback that actually helps us to position the data in the BLA filing, the type of information that you would get in a pre-BLA meeting. Again, I think very nice progress here. Again, very proud of the team here at Atara that's worked so hard on getting this regulatory filing together.
Maybe a follow up to your second point there. In the past, management suggested that if you thought you had perfect clarity on what was necessary for the FDA filing, you might be able to progress to the filing without a pre-BLA meeting. Today, it sounds like you think you need that pre-BLA meeting. I guess, we're curious, what do you expect to learn at the pre-BLA meeting that you haven't already established from all the other Type B meetings that you've had?
Yeah, maybe I can answer that one. I think it's really a stepwise aspect there that we need to have final agreement on comparability, and that will lead also to the content of the module 3. Then the pre-BLA will be just to align on the different aspects of the file in terms of content, because as we said, we have a file ready to go to EMA, but FDA is asking some different type of analysis and so on. We want to make sure that the way we put together the file or we plan to put together the file for the BLA is aligned with the FDA there.
That's why a pre-BLA meeting, we believe, and we discussed that with them, will be necessary more for what I would call maybe the administrative part, which is to make sure that the way we put the data together that we have is aligned with their expectations.
Perfect. Last question from us is on ATA3219. Sounds like the IND is on track for first quarter of next year. How long do you think it'll take from the IND to actually dosing the first patient? I think for prior CAR-T therapies, there was somewhat of a lag, maybe six months or so. Will that apply to ATA3219, or is it possible that you could dose a patient sooner than that?
Yeah, we're not going to comment on that field at this stage, so we'll do that comment at a later stage when we are reaching that point. Suffice to say that we are trying to get all the learnings we can, and there is a lot of experience in the company about auto CAR-T and CD19 CAR-T, about the best way to accelerate the timing from IND to first patient and to make sure that we have the the right type of patient that study is there. We're working on that actively as we speak, but sorry, but we cannot give details. It's too early for that.
Fair enough. Thanks again for taking our questions.
Our next question comes from Jonathan Miller from Evercore. Go ahead.
Thanks, guys, for taking my question. One on 188. I thought the MTR data you showed at ECTRIMS was very interesting, and obviously you went through it again a little bit on the call today. I understand that MTR declines are associated with clinical decline in MS broadly, but has the inverse ever been demonstrated? I mean, that is, has MTR stabilization been associated with disease stabilization or MTR increase associated with disease improvement? How much confidence do we have in this biomarker sort of being predictive in both directions, I guess is my question there.
Yeah, no, thank you very much for your questions. AJ, do you want to take that one?
Sure. Yeah, thanks for the question. I think the best way to look at it is this biomarker has been most utilized in the relapsing remitting space when you're looking at trying to make those correlations. When you're thinking about the disability improvement or resolution of symptoms in MS, remember, this is all about myelination, right? So when you look at relapsing remitting lesions that are active, you'll see MTR having significant decline. I shouldn't say substantial decline. Then when those lesions resolve, you'll see the MTR increase. That's by definition. That's the disability that's associated with that lesion is getting better, right? So in RMS, there's been connections between MTR increase and presumably myelination there and improvement in the clinical status of those patients. In progressive MS, as you know, no one's ever seen disability improvement.
That's why, you know, to the questions you've asked, it's not been shown in progressive MS. You see evidence of the MTR utilization for improvement in disability in RMS just hasn't been seen in progressive. That's why the data that we have are so unique, because if you take a look at, for example, in the chronic T2 lesions, where they're generally considered really old and many of those lesions will be considered almost dead lesions. Those lesions are where we're seeing statistically significant remyelination. Really importantly, that's associated when you see the remyelination, the patients who are having that remyelination are the ones who had disability improvement. This is the first time that people are seeing that in progressive MS, and this is why the data are so important because hints of it in relapsing remitting.
Here we're showing something really powerful in the progressive MS space.
Thanks so much. That makes a lot of sense. I guess one more on MS franchise. Just following up on the call you gave to Salim earlier in the call. When you talk about maintaining the integrity of the study, and obviously, you know, even the smaller part of the study here is randomized and double blind. Are we to assume that the blinding is going to be maintained throughout the interim analysis and therefore the amount of data that you actually have in-house is going to be limited by what the pre-specified DSMB run analysis provides you with? Like, you're not going to have a bunch of data that you're hiding from us.
This is just more about the maintaining the blind in the study and a limited amount of data being pulled out at the IA. Is that fair?
Yeah. You want to start and I'll chime in.
Sure. I think the best way to look at it is we are, as you might imagine, for any really robust randomized controlled trial, we're putting in as many controls as possible to make sure we maintain as strong a blind as possible. Of course, the DSMB, the safety monitoring team will see all those. The data monitoring team will see all the data. You know, there'll be very limited exposure to the data internally. It's not like we're looking to hide any specific information. Again, the best way to look at it is this will be conducted robustly, so we maintain the blind as much as we can. That way the power of the results at the end will be as strong as we can get.
Yeah. Again, John, I think as we say, the specifics of what we can say are going to be clarified at the time of the IA, because that depends very much on the data. That depends very much on the status of that study following the discussion with the FDA. Could it be transformed into phase II or not? I mean, there are many variables there. What we can confirm today is that this IA not only will be a very important milestone, but we'll be able to say while preserving the integrity of the study, to say not only what we are deciding based on that, but why we're deciding it to a certain extent in terms of detail.
All right. Thanks so much, Pascal. That makes sense. Maybe switching gears for just a second to ATA2271. Looking forward to seeing some of that early data at ESMO IO. Just to expand on what you said previously there. I understand this is from the lower dose cohorts, but can you tell us how many patients in total you're going to have there and whether we should expect meaningful dose response to continue beyond these cohorts we see at ESMO IO?
Yeah, I think we're not commenting at this stage on many patients and so on. You'll have to wait for a few weeks there. We'll give full details at the time. We said last time that it was really the lowest dose cohort. It's around the cohort 1 and 2 only. These are, I mean, the stepwise. Remember it was 1 million per kg for cohort 1, 3 million per kg for cohort 2, and these are the low dose there. That's why we are really focusing on safety and translational there.
I think that for us, one of the key aspects will be really the PK, because I mean, we've seen data from this type of CAR-T that are showing, you know, expansion and then the CAR-T starts to exhaust and there is no more CAR-T or at least much lower level there. If we could be able to see something different there, that would really be some proof of concept for having 1XX as a co-stimulatory domain and the PD-1 DNR, both of them having a role to play on persistence, and we see defense mechanism against the immunosuppressive tumor microenvironment there. I think that could be great if we could show that.
All right. Thank you very much.
Our next question comes from Salveen Richter from Goldman Sachs. Go ahead, Salveen.
Thank you for taking the question. This is Tommy on for Salveen. Can you just remind us of the key points of differentiation on Atara's mesothelin-targeting CAR-Ts compared to other competitors? Thank you.
Yes. Jakob, do you want to take that one?
Yeah, sure. Absolutely. For our mesothelin CAR-T, just a reminder that this is a program that we partnered with Bayer, and there are two programs in the franchise. There's the autologous program, 2271, which is currently in the clinic, and that is the ESMO IO presentation that's gonna occur here in December. There's the 3271 program, which is the allogeneic program where we're heading towards an IND filing in the second half of next year. Firstly, what both of these programs have in common is the binder against mesothelin. This is a binder that's already been de-risked by an academic first-generation program at Memorial Sloan Kettering.
We know from the first gen program that this is a safe binder, and again, we'll share data here coming at the end of this year at ESMO IO. Additionally, what we have in our programs are the 1XX co-stimulatory domain. This is a next generation co-stimulatory domain developed by Dr. Michel Sadelain at Memorial Sloan Kettering, where the idea is to innovate co-stimulation in the T cells so that you enhance in vivo expansion, persistence, and reduce exhaustion of those cells. Again, this is an important co-stimulatory domain. Additionally, both programs also have PD-1 dominant negative receptor constructed into the cells, where the cells are not at risk for the tumor suppression from tumor PD-L1 expression.
Again, this is a unique feature that could also enhance in vivo persistence and prevent exhaustion as well. The additional feature with the allogeneic program is that we're using our allogeneic EBV T cells as the cellular foundation for those allo CAR-T. I think what's really important here is that we have a lot of clinical experience. As we mentioned today, nearly 400 patients treated with our EBV allo T cell platform. These cells have a great performance in patients, a great safety profile, and importantly, we retain the intrinsic T cell receptor in those allo EBV T cells.
That's really important because, as Pascal also mentioned a few minutes ago, that those programs where you knock out the T cell receptor with CRISPR-Cas9, you're actually limiting the function of those T cells in vivo. Yes, there's this evidence from the German publication in Blood from a few months ago that shows that if you knock out the intrinsic T cell receptor, the persistence of those cells, the in vivo cytotoxicity of those cells, and the performance of those cells is not as good as if you retain the intrinsic T cell receptor. I will say another important feature, and probably really critical here, is that we do not do gene editing in our approach. We know that gene editing can have safety liabilities and issues.
We do not do gene editing in our CAR-T programs, and so we think that could also be a differentiating factor for us as well. Pascal, anything further?
No, I think you covered all the aspects there, and it's a very unique and differentiated platform there. I think not only an autologous but an allogeneic following very fast. It's very exciting indeed.
Thank [crosstalk]you. Oh, sorry. Our last question comes from Yigal. No, I'm sorry, I can't pronounce your last name. Nochomovitz. Yigal?
Nochomovitz. Hi. No worries. Hi, Pascal and team. Thanks for taking the questions. Just curious, are there scenarios where at the interim analysis for ATA188, the study could either be stopped for either overwhelming efficacy or futility? Or is the interim analysis necessarily going to result in a sample size adjustment with the study continuing?
Yeah, thank you for your question, AJ.
Yeah, there is. As with any other kind of robust interim, Yigal, there's always a possibility that you would, you know, a highly unlikely event that you'd stop for, you know, futility. There's always a possibility that you stop if you have an amazing efficacy. So it's a standard interim analysis where you have those possibilities, but the primary intent really here is adjustment in sample size. That would be our expectation.
Okay. Just a separate question. When are we going to get an update on the MATCH trial and where would this be presented?
I think we don't have the MATCH trial anymore. When we merged the two trial, that became the ALLELE. ALLELE is now the pivotal study when we merged. You remember, about now three years ago, we merged that into one study, only one pivotal study only, having both SOT and HCT cohorts.
Okay, got it. Thank you.
Any other questions?
No further questions at this time.
Thank you.
At this time, the conference has now concluded. We appreciate your attendance. You may now disconnect your lines and have a wonderful day.