Atara Biotherapeutics (NASDAQ:ATRA) Q3 2021 Earnings Call

0:01 Good day, ladies and gentlemen, and welcome to ATERRA Biotherapeutics Quarter 3, 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 Hallgren, VP, Investor Relations and Finance. Sir, the floor is yours.

0:34 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 Tuchon, President and Chief Executive Officer, Dr. Jacob Dupont, Executive Vice President and Global Head of Research and Development, Upal Kopikar, Chief Financial Officer, Dr.

1:21 A.J. Joshi, Chief Medical Officer, and Dr. Kristin Urema, Chief Commercial Officer. We will begin with prepared comments from Pascal and Jacob, 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.

2:06 Pascal?

2:08 Thank you, Eric, and thank you all for joining us this morning. We continue to make meaningful progress across our three strategic priorities, DAP cell 8188 in multiple sclerosis, and our next-generation allogeneic CAR-T programs. Today, we announce for the first time positive top-line data from a pivotal phase III allele study for TAP cell in EBV-positive 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 one year in responders, while still demonstrating a well-tolerated safety profile in line with prior results.

3:08 These data will be the basis for the imminent MAA submission in the EU and our planned BLA submission in the U.S. next year for patients with EBV-positive PTLD. We are very excited to submit in the next few days our filing for approval in Europe. And with our recently granted accelerated assessment, we anticipate a decision regarding EU TAPCEL approval in the second half of 2022. Additionally, in October, we were extremely pleased to announce our exclusive commercialization agreement with Pierre Fabre for TabCell in Europe, Middle East, Africa, and other select emerging markets for EBV-positive cancers.

3:59 We believe this partnership reinforces the commercial opportunity for TabCell in these markets and maximizes the strategic and financial value of this potentially transformative therapy. On the U.S. regulatory front for TabCell, we continue to make stepwise progress for 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 TAP-Cell in Q2 2022.

4:58 Concurrently, we continue to work on pursuing the development of TAP-Cell in additional EBV patient population with a primary focus on immunodeficiency-associated lymphoproliferative disease, IALPDs. is continuing at site in the Label Expansion Multicore Study, which is evaluating six patient populations, including four within IALPDs and two in other ABV-driven disease in the U.S. and EU. The Multicore Study data is expected in 2023, and we believe this could be a meaningful label expansion opportunity.

5:43 Turning to ATA-188, or Potentially Transformative Therapy, for Patients with Progressive Multiple Sclerosis. Last month, we presented at ECTRIMS updated Phase I Open Level Extension, or OLE, data in patients with progressive MS, treated with ATA-188 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 that would be expected based on this natural history.

6:31 The majority of SDI seen in the data presented is driven by sustained EDSS improvement, which is a primary endpoint in our Phase II randomized control of the so-called EMBOLD study. Additionally, we presented magnetization transfer ratio, MTR data, and 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 re-myelination may be the driver for clinical improvement. These potential biological basis for clinically significant EDSS improvement observed with 80188 continues to build awareness and interest in the transformative potential of 80188 in the medical community and with potential partners.

7:35 As a reminder, in the first half of 2022, We will conduct an interim analysis, or IA, to assess efficacy and safety. And 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, ATA2271 and ATA3271, partnered with Bayer, are progressing well.

8:26 Our collaborators at Memorial Sloan Kettering will present preclinical, clinical and translational data from the lowest dose cohorts of the open-label, single-arm Phase I clinical study of ATA2271 and autologous CAR-T therapy targeting mesothelin through a mini-oral presentation at ESMO-IO in December 21. Meanwhile, we continue to make progress on IND-enabling studies for ATA3271 and off-the-shelf allogeneic CAR-T therapy targeting mesothelin using next-generation PD-1 dominant negative receptors and 1XXCAR co-stimulatory signaling domain technologies for which we anticipate an IND filing in the second half of 2022.

9:19 Additionally, we plan to present new preclinical data confirming potential benefits in solid tumors for ATA3271 at CIDC in November. Turning to ATA3219 or 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 cost-imminatory signaling domain, an 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 platforms.

10:05 To further support our differentiated allogeneic artery 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 Fathanox 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 allogenic 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.

10:53 This includes $46 million for the sales of shares of common stock for our ATM facility. We believe we are sufficiently funded in the second quarter of 2023 with risk 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 a part 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 TAP-Cell, the first ever application for an allogeneic T-cell therapy in the world. and our progress in 18188 clinical studies could bring a truly transformational therapy to MS patients.

11:43 We look forward to providing more updates to you in the coming weeks. I will now turn the call over to Jacob. Jacob?

11:50 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 announce the first presentation of new positive data from the pivotal TAD cell Phase III allele study in EBV-positive 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.

12:37 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.

13:49 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 cell treatment. Next month at ASH, we will present additional data on TAB cell through several abstracts, including a second oral presentation on long-term survival from Phase II and multicenter EAP studies in relapsed refractory EBB-positive PLT, showing median overall survival of 54 months and OS at two years reaching over 86% in responders where patients experience CR or PR.

14:35 As a reminder, both pivotal data from the allele study and historical data will be included in the regulatory filings of TAB-Cell. We believe that TAB-Cell is a truly transformational therapy for these patients with EBV-positive PTLD with immediate survival is just a few months for patients who have progressed on one prior line of therapy. And the data we have shown today serves to deepen our conviction around the potential benefit the TAP cell can bring to patients. Regarding the TAP cell 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 cell products.

15:33 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 22 regarding these analyses to gain agreement on comparability for pivotal to commercial TAP cells. We've also shared the clinical data from the Pivotal Allele Phase III study along with data from supportive and historical studies. We receive productive feedback from the agency that will help to guide the structure of our BLA filings. following agreements on comparability, we plan to have a pre-BLA meeting prior to submitting the BLA for Tapsil and the EBV-positive PTLD in the second quarter of 2022.

16:29 Moving to ATA-188, our product candidate for multiple sclerosis. At ACTRIMS last month, we presented encouraging two-year clinical data from the Phase I open-label extension and new translational MTR data from the Phase 1 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.

17:17 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 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 ATA-188 who achieved sustained EDSS improvement versus those who did not, MTR for non-enhancing T2 chronic brain lesions increased.

18:23 with a trend at six 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 ATA-188 Phase I MTR data assessing normal appearing brain tissue in PPMS and SPMS patients compares favorably to saponimod 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.

19:12 As seen in the placebo group from the Phase III saponimod study data, saponimod showed slowing of demyelination-based on a small decrease in MTR versus placebo. On the other hand, ATA-188 uniquely indicates remyelination based on a relatively large magnitude increase in MTR. On slide 38, starting at six months after ATA-188 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, ATA-188 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 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 ATA-188.

20:34 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 in bold study. We believe this MTR data further support the probability of success of ATA-188 as we head towards the upcoming interim analysis in the first half of 2022, turning into 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 retains the endogenous T cell receptor. This has been shown in academic studies to increase persistence, durability and trafficking.

21:30 The safety and tolerability of our allogeneic EBV T cell therapies and platform has now been supported by clinical studies and evidence in approximately 400 patients in various disease areas. And our EVV platform enables scaling of manufacturing in stir 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'll now turn the call back to the operator to be in the QA portion of the call. Operator? Thank you. The floor is now open for questions.

22:16 If you do have a question, you may press Star 1 on your telephone keypad at this time. If your question has been answered, you can remove yourself from the queue by pressing 1. Again, ladies and gentlemen, it is Star 1 to ask a question. And our first question comes from Salim Saeed from Mahuto. Go ahead.

22:40 Hi, thanks guys for all the color and congrats on the progress. So a couple from me on ATA-188. So Pascal, Jacob, when we get the data in the first half of 22, historically in multiple sclerosis trials, I think folks generally understand companies need two trials to file for regulatory approval. But progressive and multiple sclerosis, there's also an unmet need. And I think it's pretty established that you guys will let us know if you're going to have a large increase in N here or a smaller increase. And I'm just wondering, is a fair way to interpret this is that if you say, hey, we're going to increase this by a large N, that the p-value you're seeing is less than 0.01.

23:29 and you only need one trial. And if it's a smaller increase, the p-value is something like, you know, you think you can get to a .05 or less. And just wondering if you can actually give us that p-value when you disclose the data. And then the second question, just more around the limited disclosure that we're going to get in the first half of 22. 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? And the reason why I ask is I think some investors would argue here that it's more capitally efficient to disclose more data. So I'm just sort of curious how conceptually you're thinking about that. Thank you.

24:10 Thank you, Salim, for your question. I'll ask A.J. to start answering there and starting with a second question because it will give color to the first one there. A.J.? ?

24:20 Sure. Thanks for the question, Celine. You know, yeah, starting with that second question, maybe we can just give an overall kind of view on this. So, as you know, the IA for this randomized placebo-controlled Phase II study, we're going to hit both efficacy and safety criteria as well as some additional biomarkers. And 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 three-month time. So it's going to be a fairly large data set for us there. And the objective, as you kind of alluded to, is to adapt the sample size, which at this stage is 80. But, you know, we could certainly – the plan is to potentially adapt it to a larger size depending on the trend we see and possibly discussions with the FDA.

25:07 And what we're saying is that 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. So we are going to 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. But we can emphasize that the IA-based rationale for any adjustments we're going to make in both studies will be made clear, but we still have to maintain the integrity of that double-blind study, and that kind of leads into that last question that you were asking. So 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. So at the time of the IA, let's say we see a trend of EDSS improvement in the active ATA188 arm that's similar to what we observed in the Phase IA study.

26:04 And then we see a trend for placebo that's pretty much what we expected in our modeling. So at that point, we'd likely either decide to make no or minimal change to the sample size. except if we believe that, you know, 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. So this is really, again, it's really about this is a strong, robust Phase II. It's still fully placebo-controlled, so, you know, not like an oncology setting where you and MS, we're going to have to do as much as we can to maintain the integrity of that study. So that's the main rationale behind giving details on the rationale but not details on the data itself.

26:56 So, you know, that kind of leads into your second question about will we be disclosing p-values. We're not going to be discussing specific p-values or the statistical methodology at this point for the study, and we wouldn't be disclosing that at the IEA.

27:13 And 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 not the situation of the FDA. But 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.

27:44 Super helpful. Thanks so much, guys. Congrats on the progress. And our next question comes from Matt Phillips from William Blair. Go ahead, Matt.

27:57 Hi, everyone. Thanks for taking my question. I just wanted to try to clarify some of the regulatory discussions around CMC. So any color on what the CMC team is focused on at this point? Because you said on the Q2 call that you were aligned regarding comparability approach. and so just kind of curious what additional information you're looking for. And then again, just to make sure I understand the sequence of events correctly, you're going to 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?

28:36 Thank you, Matt. And maybe I'll start and NGCOM can chime in if needed there. As you said, we have reached agreement on the methodology. We've presented during the recent IP in October this new comparability analysis. And you may remember we sent you to 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. and we believe and we've shown in our analysis that this set of data demonstrate comparability between the pivotal study process and the Internet commercial process version. Keeping in mind, of course, as you may remember, that in reality these process differences between these manufacturing process versions are minimal.

29:22 They're really minimal there. But we analyzed all the batches, presented all these data, an immense amount of data to the FDA. So what the FDA has asked is additional data analysis related to a few attributes there. And we will provide them because they have the data already, but they ask us to do additional analysis. So we'll do this additional analysis. We'll provide the FDA with this analysis for these data already submitted. And then 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. And then once we've got to that level of discussion and alignment with the ADN 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, and then we'll be able to file for BLA.

30:17 So that's the sequence of events there that we are planning based on this discussion with the FDA. Does it answer your question?

30:24 Yeah, no, thanks. Thanks, Pascal. That's helpful. Then 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 was included in kind of these response rates, if you can remind me on that.

30:48 Yes, Jacob, do you want to answer that one?

30:53 Yeah, so Matt, thanks for the question. So we haven't included that particular detail in the abstract at this point in time, but 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. And this is, of course, by independent oncologic and radiographic assessment, so this is really independently reviewed. And I will say that most of the responses were with the first therapy, but, of course, we can switch lots. But those details were not included in the current abstract presentation.

31:43 But you can expect, it's an oral presentation at ASH, so you can expect much more detail at ASH.

31:49 Great. Thank you. And our next question comes from John Newman from Canaccord. Go ahead, John.

32:00 Hi, guys. Good morning. Thanks for taking my question, and congrats on all the progress, especially in Europe with TAPSEL. 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. But I just wanted to ask, my understanding is that the median follow up for this study at this point is very, very long. And 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, but I just wondered if you could perhaps just comment a bit about the follow-up for the study. Thanks.

32:56 Thank you, John, for your question. Jacob, do you want to take that one?

33:00 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-month duration of response data, which again is is required for regulatory approval, which is why we did this most recent data cut. And so we do, again, have this durability of response data, as I mentioned earlier in my comments, that we think are quite encouraging. And I think the 89% survival of responders at one year is quite encouraging.

33:47 So 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. And 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. So 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.

34:39 Okay, great. I have one additional question, sort of a general question on ATA-188. 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.

35:14 Thank you, John, for your question. I'll start, and then AJ or Jacob, 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 two 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 and to our knowledge, only one has tried to develop on the DSS improvement for the phase three. That was a May Day study there with unfortunately that study failing there. So it was very important there that we talk with the FDA and we align with them and they did say that sustainability improvement is an important primary endpoint for and Progressive MS, and they prefer to have EDSS improvement.

36:11 That's why we change our primary criteria in the EMBAL study to be sustained EDSS improvement. So 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 is trying to look at this sustained EDSS improvement. But that's a first that has been aligned with the FDA. Does it answer your question, John? Yes, thank you. And our next question comes from Tessa Romero from JP Morgan. Go ahead.

36:50 Hey, guys. Good morning. A couple of questions from me this morning on the CAR T programs, if I could. So just thinking a little bit about the mesothelian CAR T program, ATA 2271, 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 about from the prior MSK data and also your allogenetic program? What would be a win scenario in your view here? And then my second question is on the ATA-3271 allogenetic program. What are the gating factors to IND submission at this point?

37:37 Thanks so much.

37:39 Thank you very much for your question. Jacob, do you want to take the first one?

37:43 Yeah, absolutely. So, Tessa, thanks for your question. So, as mentioned, we're excited to announce that we have a mini oral presentation with our collaborators at Memorial Soketarik for the autologous mesothelin program. We think that our Allocart 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. And, of course, this first study is for the auto program, and then we have the following allogeneic one using our EBD T cell platform. And, 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. So, at ESMO I-O, our collaborators at Sloan Kettering will present preclinical data for the program, but also clinical data from low-dose patients. So, you'll see safety there.

38:53 and others, 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. And then I also think, you know, these questions of persistence of the cells is really important. and the Allogeneic Program 3271. Just one comment. We are having a presentation here at CITSE very shortly with preclinical data, updated data for that allo mesothelin program. So that will be a poster presented at CITSE.

39:39 And then we're very much on track with the R&D filing in the second half of next year. And I will say, you know, as with any IND, you have to get all of your studies ready for the IND filing, including, of course, for this type of therapy, the manufacturing aspects for this type of program. But I will say everything is moving ahead very well with our partner buyer here, and 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. And, again, we're targeting a Q1 IND of next year.

40:23 And, Tessa, maybe two additional points. We are very excited about this program, and so 3271 in particular. One aspect that is very unique to ATARA, in fact, two aspects. First one is this 3271 is going to be made, is being made right now, in still-tongue bioreactor. That's a big first for an allogenic CAR-T or CAR-T in general there. And I think that's why it's taking the time to put that together because that's a big first, but we have already evidence at some early stage that we can make this allogenic CAR-T into still-tongue bioreactor, which is going, we believe, to change radically The manufacturing efficiency of allogenic cell therapy manufacturing. So watch the pace there.

41:11 The other aspect is the fact that we are maintaining TCR in 3271. 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 mesothelin CAR T cells that were edited to lose TCR and PD-1 expression. And what was very interesting in this phase one study, that the authors could not detect CAR T cells in 12 of the 15 patients and the only three patients after just a few weeks. And 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. So for us, it's a clear evidence that if you maintain the TCR, you have more persistent. If you delete the TCR or you modify the TCR, the endogenous one for allogeneic CAR-Ts for gene editing, not only you create a 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.

42:33 Does it answer your question?

42:35 Absolutely. Thanks so much for the color. Pascal and team really appreciate it. and our next question comes from Phil Nadeau from Cohen and Cohen. Go ahead, Phil.

42:51 Hi, good morning. Let me add my congratulations on the allele data. A few questions from us on TAP-Cell. 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. So, appreciating that you have alignment. How confident are you that you know exactly what the FDA wants and that there's not going to be a newer request when you talk to the agency in Q1?

43:27 Thank you, Phil. I'll start and Jacob will chime in. I mean, first of all, like I say, we are 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 and 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 US 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. And 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 various type B meetings that we are doing with the CMCL review team. And we are making progress, stepwise progress there.

44:18 So we certainly are understanding their questions, and we're going to put together this new analysis they're asking for and 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, and it's really around new analysis more than trying to create new data at this stage. Jacob, anything to add?

44:47 Yeah, and just to maybe amplify that as well, I do think, as you see, we're making this stepwise progress. So at the last quarterly call, we announced that we 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. And the great news is we can do that. We have all those lots. So that was great clarity to get from the agency. And 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.

45:38 So again, this was an area of much discussion, and we came to agreement there. And 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. So, again, I think there's clear evidence of progress here, and I think we are confident in that progress. And as Pascal says, it's really incredible as a pretty small company here that we're completing our first regulatory filing and submitting in Europe here, as Pascal mentioned, within the next couple of days. But 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.

46:36 So 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. And, again, very proud of the team here at Atari that's worked so hard on getting this regulatory filing together.

47:11 And 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. So 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?

47:39 Yeah, maybe I can answer that one. I think it's really a stepwise aspect there that We need to have that final agreement on comparability, and that will lead also to the content of the module 3. And 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 and some different type of analyses and so on. So 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. So that's why the 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.

48:28 Perfect. Then last question from us is on 3219. Sounds like the IND is on track for the first quarter of next year. How long do you think it will 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 3219, or is it possible that you could dose a patient sooner than that?

48:51 We're not going to comment on that 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 Autocarty and CD19-Carty, about the best way to accelerate the timing from IND to first patient and to make sure that we have the right type of patient that studies there. So we're working on that actively as we speak, but we cannot give details. It's too early for that.

49:25 Fair enough. Thanks again for taking our questions. And our next question comes from Jonathan Miller from Evacor. Go ahead.

49:36 Thank you guys for taking my question. One on 188. I thought the MTR data you showed at Ekstrom's was very interesting and obviously went through it again a little bit on the call today, but I understand that MTR declines are associated with clinical decline in MS broadly, but has the inverse ever been demonstrated? 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 predicted in both directions, I guess, is my question there.

50:15 Yeah, no, thank you very much for your questions. AJ, do you want to take that one?

50:20 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. And 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. And then when those lesions resolve, you'll see the MTR increasing. By definition, 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.

51:17 And that's why, you know, to the questions that you've asked, It's not been shown in progressive MS. You see evidence of MTR utilization for improvement in disability in RMS just hasn't been seen in progressive. And 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 have had statistically significant remyelination, and really importantly, that's associated when you see the remyelination, the patients who are having that remyelination are the ones who had disability improvement. So 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, but here we're showing something really powerful in the progressive MS space.

52:15 Thanks so much. That makes a lot of sense. One more on MS franchise, just following up on the call you gave to Selim earlier in the call. When you talk about maintaining the integrity of the study, obviously 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? You're not going to have a bunch of data that you're hiding from us. It is more about maintaining the blind in the study and a limited amount of data being pulled out of the IA? Is that fair?

53:04 Do you want to start and not chime in?

53:07 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. So, of course, the DSM, the safety monitoring community will see all those. The data monitoring community will see all the data. There'll be very limited exposure to the data internally, so it's not like we're looking to hide any specific information. But again, the best way to look at it is this will be conducted robustly, so we maintain the blind as much as we can. So that way, the power of the results at the end will be as strong as we can get.

53:49 Yeah, and again, John, I think, as we say, the specifics of what we can say are going to be clarified at the time of the IEA because that depends very much on the data. It depends very much on the status of that study following the discussion with the FDA. Could it be transformed in the face or not? I mean, there are many variables there. What we can confirm today is that this IEA 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.

54:25 All right, thanks so much, Pascal. That makes sense. Maybe switching gears for just a second to 2271, 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?

54:55 Yeah, I think we're not commenting at this stage on how many patients and so on. You'll have to wait for a few weeks there. We'll give full details at the time. But we said last time that it was really the lowest dose cohort. It's around the cohort 1 and 2 only. So these are stepwise. Remember, it was 1 million per kick for cohort 1, 3 million per kick for cohort 2. and these are the low dose there. So that's why we are really focusing on safety and transnational there. I think for us one of the key aspects would 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.

55:44 and if we could be able to see something different there that would really be some proof of concept for having 1XX and as a costimatory domain and the PD-1 DNR, both of them having a role to play on persistence and I would say defense mechanism against immunosuppressive tumor microenvironment there. So I think that would be great if we could show that. Thank you very much. and our next question comes from Salveen Richter from Goldman Sachs.

56:17 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.

56:35 Yes. Jacob, do you want to take that one?

56:38 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 going to occur here in December. And then 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. So firstly, what both of these programs have in common is the binder against mesothelin. So this is a binder that's already been de-risked by an academic first-generation program.

57:30 at Memorial Sloan Kettering. So 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. So this is and the next generation co-stimulatory domain developed by Dr. Michelle Sadelein at Memorial of St. 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. So again, this is an important co-stimulatory domain. Additionally, both programs also have PD-1 dominant negative receptor constructed into the cells where you do not, where the cells are not are at risk for the tumor suppression from tumor PD-L1 expression.

58:32 So, again, this is a unique feature that could also enhance in vivo persistence and prevent exhaustion as well. And so, the additional feature with the allogeneic program is that we're using our allogeneic EBVT cells as the cellular foundation for those Allocard T. And 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.

59:25 And that's really important because, as Pascal also mentioned a few minutes ago, that those programs where you – where you knock out the T-cell receptor with CRISPR Cas9, you're actually really limiting the function of those T-cells in vivo. And 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. and 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.

1:00:27 We do not do gene editing in our CAR T programs and so we think that that could also be a differentiating factor for us as well. Pascal, anything further?

1:00:40 No, I think you cover all the aspects there, and it's a very unique and differentiated platform there, and also having not only an autologous but an allogenic following very fast. It's very exciting indeed. Thank you. Oh, sorry. And our last question comes from Yugal. No, I'm sorry, I can't pronounce your last name. Nachav. Movis, Yigal.

1:01:14 Hi.

1:01:15 No worries. Hi, Pascal and team. Thanks for taking the questions.

1:01:19 Just curious, are there scenarios where at the interim analysis for ATA-188, 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?

1:01:38 Thank you for your question. Ajit?

1:01:41 Yeah, as with any other kind of robust interim you got, there's always a possibility that you would, you know, highly unlikely event they'd stop for futility. You know, and our intent would not, there's always a possibility that you stop if you have an amazing efficacy realm. 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.

1:02:10 Okay, and then just a separate question. When are we going to get an update on the MATCH trial, and where would this be presented?

1:02:20 I think we don't have the MATCH trial anymore. When we merged it to trial, that became the ALIL. So ALIL is now the pivotal study when we merged. If you remember about now two years ago, we merged that into one study only, one pivotal study only, having both SOT and HCT codes.

1:02:39 Okay, got it. Thank you.

1:02:45 Any other questions? And no further questions at this time. Thank you. At this time, the conference is now concluded. We appreciate your attendance. You may now disconnect your lines and have a wonderful day.