Good afternoon, everyone. Thank you for standing by, and welcome to the Atara Biotherapeutics First Quarter 2021 Financial Results Conference Call. If anyone should require operator assistance during the conference, please press star zero from your telephone keypad. Please be advised that today's call is being recorded. I'd now like to hand the call over to Eric Hyllengren, Vice President, Investor Relations and Finance at Atara Biotherapeutics. Please go ahead, sir.
Thank you, Rob. Good afternoon, everyone, and welcome to Atara's First Quarter 2021 Results Conference Call. Earlier today, we issued a press release announcing our first quarter financial results and operational progress. This press release and an updated investor presentation 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, Joe Newell, Chief Operations Officer, Dr. AJ Joshi, Chief Medical Officer, and Dr. Kristin Yarema, Chief Commercial Officer. We will begin with prepared comments from Pascal and Jakob, then open up the call for your questions.
We would like to remind listeners that during the call, the company's management will be making forward-looking statements. Actual results could differ materially from those stated or implied by our forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's press release and the company's SEC filings. These statements are made as of today's date, and the company undertakes no obligation to update these statements. Now I'd like to turn the call over to Pascal. Pascal?
Thank you, Eric, and thank you all for joining us this afternoon. We are off to a strong start in 2021, making progress on all three of our strategic priorities, tab-cel, ATA188 in multiple sclerosis, and our next-generation allogeneic CAR-T programs. We are moving ahead to deliver on key milestones this year, including the expected tab-cel BLA and MAA filings, progress on the ATA188 program, especially presentation of new clinical and translational data from our phase I open-label expansion study, and first clinical data on our mesothelin CAR-T program in advanced mesothelioma. For tab-cel, we are in active discussions with the FDA on the content of CMC module three, including methodologies and data to assess comparability between the product used in the pivotal clinical study and the intended commercial product.
Supported by our breakthrough therapy designation, we have been having regular dialogue since January with the FDA on the CMC module 3, and most recently, a teleconference last Friday, where we discussed key aspects of our comparability data package. We believe that we have provided the FDA a robust data package to demonstrate comparability between various process versions of tab-cel, and we are encouraged by the ongoing interactions as we work towards aligning with the FDA. Atara is a trailblazer for allogeneic T-cell therapy as a whole, and as such, we are paving the way for the first-ever allogeneic off-the-shelf T-cell therapy for Atara and for our industry. We understand that doing so will take time, effort, and constructive discussion with regulators, and we are well on our way. Meanwhile, a recent analysis shows that duration of response in our ALLELE study is maturing as anticipated.
We have a large number of responders followed now for at least six months and a safety profile consistent with previous published data with no new safety signals. As a reminder, we will present data from the Phase III ALLELE study at an appropriate congress in Q4 2021. In summary, we are making progress to align on comparability with the FDA and are confident we will do so. Pending this alignment, we plan to complete our BLA submission for PTLD in the third quarter of 2021. In the EU, where tab-cel has PRIME designation, we have submitted a letter of intent to the European Medicines Agency or EMA, thereby starting the process of submitting an EU marketing authorization application, or MAA, for tab-cel in patients with EBV+ PTLD , which we expect to complete in Q4 2021.
In parallel, there has been strong interest from potential partners for commercialization of tab-cel in Europe and continued support from physicians and medical experts. We continue to invest in our U.S. commercial readiness activities, mainly disease state education and payer access preparation, in anticipation of tab-cel approval and planned launch in the first half of 2022. We are also building tab-cel inventory and are on track to reach our goal of over 95% of PTLD patients covered at the time of commercial launch. With regard to our tab-cel phase II multi-cohort study in patients with other EBV-driven cancers, we continue to actively open clinical study sites. Evaluation of potential study participants is well underway. The six study populations, of which the target, the largest two are EBV+ AID-LPD and EBV+ PID-LPD, may support meaningful label extension beyond PTLD.
Turning to ATA188, our transformative product candidate for patients with progressive form of multiple sclerosis. We continue to make progress in enrolling the phase II randomized double-blind placebo-controlled study or RCT. We are on track to conduct an interim analysis for this study in first half 2022, including efficacy and safety in patients with progressive form of MS. Following this interim analysis, we expect to have further discussion with the FDA regarding potential study adjustment for pivotal intent. These are important discussions from both a regulatory and strategic perspective for the program and could provide optionality on how we advance development. Momentum continues to build in the community, reinforcing the association between EBV and MS. These contributed to Atara successful approval of a clinical trial application for the phase II RCT in Canada in the first quarter of 2021.
We also continue to see significant interest from a number of large companies regarding a potential collaboration involving ATA188. As a reminder, in the second half of 2021, we plan to present long-term two-year clinical data from the phase I open label extension or OLE, as well as translational data from the phase I study. Moving to our CAR-T portfolio, and first, our mesothelin franchise program, ATA2271 and ATA3271. These mesothelin-targeted CAR-T products are benefiting from a global strategic collaboration with Bayer, which is fully underway with positive alignment with our partner and a successful launch of our joint governance and activities. For ATA2271, our autologous mesothelin CAR-T program, the phase I clinical study has completed enrollment of the first cohort. First clinical data is expected to be presented in an appropriate forum in Q4 2021.
The off-the-shelf allogeneic version of this mesothelin CAR-T program, ATA3271, using a PD-1 Dominant Negative Receptor and 1XX CAR costimulatory signaling domain through our EBV cell platform, is currently in IND-enabling studies, work that Atara is doing. Subsequently, Bayer will submit the IND expected in Q2 or Q3 of 2022 and lead clinical development and commercialization. Turning now to ATA3219, our allogeneic CAR-T for patients with B-cell malignancies. We plan to submit an IND in Q4 2021 or Q1 2022 in line with our strategic goal to develop this asset as best-in-class in B-cell malignancies. Moving to our financials, with regard to our cash position and runway, we ended the first quarter of 2021 with $435 million in cash.
With this cash balance and projected revenues from U.S. tab-cel sales, we believe we are sufficiently funded into 2023, inclusive of expenses for the BLA filing and U.S. commercial launch of tab-cel. As we head into the second quarter of 2021, I've been reflecting how far Atara has come from this time a year ago. With the pandemic just beginning to gain foothold in the U.S. back then, we focused on our staff and collaborators' safety in order to continue our mission of bringing transformative therapies to patients. We work closely with clinical study sites and with our manufacturing and logistics partners to ensure patients will continue to access our therapies in our studies. Through the hard work of our Atara team, we are on path to file our tab-cel BLA in the third quarter of this year and bring this life-saving medicine to patients in need.
I will now turn the call over to Jakob. Jakob?
Thank you, Pascal. As Pascal described, we have made steady progress across all three of our strategic priorities in the first quarter. For tab-cel, we are in active discussions with the FDA and are aligned on key aspects of comparability with regulators. We are the first allogeneic T-cell therapy company to be ready to submit a BLA for FDA approval. The discussions we are having with FDA are part of our BTD status prior to BLA submission and may set precedents for other allogeneic products that follow. At this time, we are focused on the CMC module three with the FDA, and we believe that we have provided a robust data package to determine comparability between various process versions of tab-cel and are encouraged by the ongoing interactions.
We expect to align on comparability and then we plan to complete our BLA submission for PTLD in the third quarter of this year. Our confidence is reinforced by the fact that tab-cel is truly remarkable for an investigational product being developed for an ultra-rare disease, in that it already has many years of clinical experience with nearly 300 patients treated with life-threatening EBV positive diseases in clinical trials, as well as expanded access in single-patient use settings, including 150 patients with EBV positive PTLD. This clinical experience shows that tab-cel's efficacy and safety profile in PTLD patients is consistent from both an efficacy and safety perspective, irrespective of product version and across studies, including the pivotal ALLELE study interim analysis data. We are presenting combined long-term overall survival data from clinical studies of tab-cel at two medical congresses.
Data from three clinical studies of tab-cel demonstrate that patients with EBV+ PTLD following either HCT or SOT that is relapsed or refractory to initial treatment have over 80% two-year survival, whether they achieved a complete or a partial response. For perspective, these patients with EBV+ PTLD after HCT or SOT have a median survival of only two to three months in the second line and beyond treatment setting without tab-cel treatment. These data suggest the potential transformative impact for these patients in great need, and that tab-cel may provide an effective treatment options marked by long-term overall survival, regardless of partial or complete response. Of note, the British Society of Haematology just released updated guidelines for the management of EBV+ PTLD. These guidelines specifically recommend the use of EBV+ or EBV specific CTL immunotherapy for relapsed refractory PTLD, including CNS PTLD, where available.
Tab-cel data were particularly referenced among several datasets. These guideline recommendations are similar to the NCCN guidelines for non-Hodgkin's lymphoma that also recommend EBV specific CTL therapy like tab-cel for relapsed refractory EBV+ PTLD . Now, with regard to ATA 188 for multiple sclerosis, I am pleased to report we are making progress enrolling the phase II randomized double-blind placebo-controlled trial evaluating the efficacy and safety of ATA 188 in patients with progressive forms of multiple sclerosis. Importantly, we are on track to conduct an interim analysis of the phase II RCT in the first half of 2022, including efficacy and safety. As Pascal mentioned, we expect to have further discussions with the FDA regarding potential study adjustments for pivotal intent following the interim analysis. Based on the current sample size, we expect to complete enrollment of this phase II study in the first half of next year.
In addition, we plan to present long-term two-year clinical data from the phase I open label extension, as well as translational data from the phase I study in the second half of 2021. We are making good progress on translational work looking at possible correlation with clinical response. Finally, w e filed and received approval of a clinical trial application for the phase II RCT in Canada, and we look forward to opening sites in Canada soon. Turning now to our CAR-T programs, o ur strategic collaboration with Bayer for our mesothelin CAR T-cell therapies, ATA2271 and ATA3271 for treatment of solid tumors is progressing well. We continue to work collaboratively with Bayer to move both programs forward.
What differentiates Atara from other approaches is Atara's CAR-T programs are based on our allogeneic EBV T-cell platform and our ability to leverage new technologies such as novel costimulatory domains like 1XX, and novel armoring technologies like PD-1 dominant negative receptor to improve efficacy, persistence, and durability of response. We believe this could address limitations of autologous and other allogeneic CAR-Ts. Specifically, our platform's use of starting materials that are long-term central memory T cells that have previously encountered EBV are intrinsically less prone to differentiation and exhaustion. As such, homeostatic proliferation and fitness is already embedded at the core of our technology. This, together with Atara's 1XX signaling domain, which prevents premature differentiation and exhaustion, represents an ideal combination. In fact, at this year's AACR meeting, our collaborator, Dr. Michel Sadelain from Memorial Sloan Kettering Cancer Center, presented a plenary talk on advances in CAR-T.
Dr. Sadelain featured 1XX as a potent new costimulatory domain for CAR-T with remarkable ability to support functional persistence. Specifically, he presented in vivo data from Dr. Jonas Madsen and colleagues of a mesothelin CAR-T with 1XX domain that revealed impressive survival outcomes in a mesothelin-expressing ovarian cancer tumor model. 1XX outperformed mesothelin CAR-Ts designed with either CD28 Zeta or 4-1BB costimulatory domains. With regard to ATA3219, we are progressing with various IND enabling activities to submit an IND in the fourth quarter of this year or the first quarter of next year. As a reminder, ATA3219 is our next generation, off-the-shelf allogeneic CD19 CAR-T utilizing the 1XX technology without the need for TCR editing for the treatment of B-cell malignancies. We are excited about the technology, and our strategic goal is to develop this asset as a potential best-in-class product for B-cell malignancies.
I would like to extend my gratitude to our Atara staff, collaborators, patients, caregivers. Atara's success in bringing these life-saving therapies to patients is because of you. I will now turn the call back to the operator to begin the QA portion of the call. Operator?
Thank you. Our first question today will be coming from the line of John Newman with Canaccord Genuity. Please proceed with your question.
Hi, guys, t hanks for taking the questions, and congratulations on the continued progress. A question I have is regarding the tab-cel filing. Pascal, if I can remember correctly, last year when you and Atara disclosed the data on tab-cel, I think you had also mentioned that you had come to an agreement or an understanding with the FDA in terms of the number of patients that they would like to see for the filing. I'm just curious if that was the case. The reason I'm asking is because it's always seemed to me like the discussion you're having regarding the previous data generated at Sloan Kettering and the data that you've generated, is more around the analysis rather than the amount of data. I just wondered if you could discuss that. Thank you.
Thank you, John, for your question. Jakob, do you want to start answering that, and I'll make another comment after that?
Yes. We do believe that the guidance still holds, that the number of patients that we've enrolled in ALLELE is sufficient for the BLA filing. What we've been working on, which Pascal reported on today, is that we now know more about the durability of response of these patients, and that data is looking good. Now, of course, we still are working on this issue of comparability, which will help us to get to the point of initiating the BLA, and it will also help us to position the historical data relative to the pivotal data from the ALLELE study, where we either present the historical data in parallel in the BLA filing or in a pooled analysis. Pascal?
Yeah, just to clarify, as we said in the past, John, that we are planning a data cut in Q2 with new data available in Q3 to be able to complete the clinical module, module 5, for the BLA submission. What we're doing meanwhile is really to work on the CMC module 3. Does it answer your question?
Yes. Thank you.
Thank you. Our next question comes from the line of Salim Syed with Mizuho. Please proceed with your questions.
Great, g ood afternoon, guys. Thanks for all the color and congrats on all the progress. A couple from me on ATA188, if I can. The first, maybe this is for AJ or Jakob perhaps, or Pascal. As we approach the interim data in the first half of 2022, I'm just curious how you guys are thinking about the overall program here for ATA188. What do you need to see on that interim that would make you confident that you can convert this to a registrational study and apply for approval just on this one trial? Then the second question is more just on your discussions with the FDA. If I recall, on the last call, you had mentioned in the coming months you'd have some discussions on whether SPMS and PPMS would be treated as one population or two.
Have you had those discussions, or is there any update you can provide there? Thanks so much.
Thank you, Salim, for your two questions, so f irst question, AJ?
Sure, and then t o some extent, Salim, they're a little bit interrelated. When you talk about the interim analysis, there's two elements of it. In our field for what would make this potential registrational trial, it starts with alignment with FDA on that patient population we talked about earlier. Whether they want us to look at this as two separate progressive MS populations or, as we've articulated, a single non-active progressive MS population, because d epending on how that answer comes out, we will then take a look at the interim analysis data. There, when we see the data, again, you know, we have a specific SAP that's going to govern how we approach this. When we see the data, we're going to look to potentially adjust the sample size to make sure we have the best chance of hitting the right power for the study.
Now, if the FDA, for example, has given us good alignment around that patient population, we might have a small adjustment in sample size to make this a robust phase III study or maybe a larger adjustment in sample size if we think that there's an opportunity to essentially turn this into one of two pivotals. Whether this could be the only pivotal, I think that would be a great kind of grand plan, but I think that would really be dependent on lots of conversations with FDA. I think our base case is strong phase II, good potential to turn this into a one of two pivotal programs, depending on those discussions with FDA and the interim analysis. You know, the last piece that you mentioned would really be, you know, would be amazing, but I think that's not really something we anticipate as a single study just yet.
Yeah, and maybe to also answer your second question a bit more in detail. What we've done recently, we had very nice interaction with thought leaders, medical expert of MS. That in fact, I've worked with different kind of consensus position on the patients with SPMS and PPMS there. These experts are all clear, that this is the same disease, and this is the same evolution of these patients there from a pathophysiological aspect there. We are reinforcing our belief with this expert position that has been communicated publicly, and now we are planning an interaction with the FDA, leveraging these expert positions to discuss with them whether it could be one or two population from a pivotal point of view. It doesn't change anything on the phase II.
It's just as AJ just say, we want to leverage this phase II in potentially transforming this into a phase III pivotal study. We need to have this alignment about is that one population or is it two population in that study? We are very encouraged by the expert view on this particular question. Does it answer your question?
Yes, it does. Thanks so much, guys, a ppreciate it.
Thank you, Salim.
Our next question is coming from the line of Jonathan Miller of Evercore ISI. Please proceed with your questions.
Hey, guys, t hanks so much for taking the questions. Just a couple quick ones, I guess, ju st to clarify, it seems like the tab-cel BLA still expected 3Q, obviously, you're having all these interactions with the agency, but it feels like there's still some Ts to cross. When do you know for sure that you'll be able to file on time? Is that the sort of thing that we're not actually going to know until the filing comes in 3Q? Secondly, the tab-cel multi-cohort study is opening sites, but are you enrolling and dosing yet? What's the timeline look like for actually getting patients into those cohorts? Do you have a sense on when we could hope to see the initial data from those most important first couple cohorts?
Then just switching gears a little bit on mesothelin CAR data coming in Q4, is it fair to expect enough patients there to get a sense for ORR, or is this going to be really a very small cohort and we shouldn't be expecting to get a robust ORR from it? Will we get persistence data at that point to complement the AACR presentation that you were talking about? What can we expect out of that initial mesothelin presentation? Thanks.
Okay. Thank you, John, for your three question. Let's start with the first one. Jakob, do you want to address the first one about the when we will know exactly whether we can file and complete the BLA?
Yes, absolutely. John, thank you so much for your question, so b ecause of our BTD status, we benefit from a number of active interactions with the FDA to speak about this comparability issue. We've had a number of Type B meetings and informal calls with the FDA over the last several months to discuss comparability and other topics related to that CMC Module 3. As we've described, these are progressing well. The active dialogue with the FDA has to be taken into context because we are bringing forward the first allogeneic T-cell therapy for a submission for an FDA approval. We think with these discussions, we're making good progress on comparability. We, as Pascal mentioned, are also working towards an additional data cut to complete that module 5.
As we mentioned, we are still moving towards that completion of the BLA filing by Q3 of this year, obviously, with these active engagements with the agency on comparability.
Yeah, and just to add on that, I think we are really according to our plan. We're working on these different aspects, I would say in parallel, both the clinical and the CMC part. We are working ahead to move into that BLA filing in Q3. Moving ahead with different discussion with the FDA, we'll continue to transparently communicate with our investors, and the key analysts there about our progress there. Today we are really moving ahead for that particular BLA into Q3 2021. Your second question was around the multi-cohort study. AJ, do you want to address that one?
Sure. This is a study, it's a good question. This is a study that had some COVID-19 impact in terms of the initiation of our sites. We have not enrolled a patient yet. However, we have really started activating initiating sites at a very good pace now. The early pace was slow related to COVID-19 because this was a study that we were starting up in the middle of COVID. That's where we took now the bit of an impact, but the most recent scenario has been that we've opened up a bunch of sites. We would expect now the enrollment to get onto the pace that we were anticipating, and t hat still leaves us with the same target timeline that we'd given previously of data coming out, which is 2023.
Does it answer your second question, John?
Yeah, absolutely, t hank you, and then o n mesothelioma.
Yeah. The first question on the meso CAR-T and what to expect at the end of the year, Jakob?
Absolutely. As Pascal mentioned in the introductory remarks, we have enrolled the first cohort on the mesothelioma, the autologous CAR-T, the 2271 program. We're certainly collecting safety data there. We will also have tumor assessments. Of course, these are relatively small cohorts of patients, but we will certainly get response data. You know, tumor assessments are built in at regular intervals in the protocol, and we will also get some sense of how long the patients stay on study. Then, some of the translational elements around persistence of the cells, in the bloodstream of patients, will also be something that we'll be able to report out on as well.
Yeah. I will add that this is very exciting type of clinical data because that's for the first time ever that a CAR-T with a PD-1 DNR and 1XX as a costimulatory domain is being used in patients in the U.S. We're all very eager to get a view of this data and to share that with you at the appropriate time, because we think that's very exciting as we believe that we are really building these CAR-Ts with the mesothelin binder, the FTAV, the PD-1 DNR and 1XX, are the best way to address solid tumors and of course today's advanced mesothelioma, where we are testing the product in. Beyond that, we intend to go in other type of tumors, so a v ery exciting time indeed.
Our next question is coming from the line of Anupam Rama with JP Morgan. Please receive your question.
Hey, guys. How are you? This is Tessa on the call tonight for Anupam. Thanks for taking our question so j ust one from us. As we are thinking about the commercial potential of ATA188 in MS, as it stands today, is this a program that Atara is thinking about partnering ex U.S., say in Europe, similar to what you guys are planning to do for tab-cel? Thanks so much.
Thank you, Tessa, for your question. I'll address it. We are now in phase II in this randomized control trial. We're also moving ahead on a lot of translational work that is pretty exciting, and we will come in first half 2022 with the interim analysis data plus some other data that we believe will allow different things. One is, of course, this discussion with the FDA on the potential to transform this phase II into a phase III and discuss about further steps in a pivotal study. We think it'll be the right time also to discuss this data confidentially with potential partners. We are already engaged with a number of companies, and as I said during my remarks, a number of them are extremely excited about this potential for ATA188 to be a big game changer in the field of MS there.
This discussion are progressing. We'll have further data there, but the idea is that we believe we would benefit in terms of value creation from having a partner for us, with us for this pivotal study type of program to address not only pivotal in PMS, in progressive MS, but also pivotal in relapsing MS, where we believe the product has a great potential as well, and maybe some other disease there, so I think a partner will be important, and we are not, at this stage, going to communicate on what type of partnership, but let's just say that this is a partnership we believe will allow us to accelerate and expand the development of ATA188 across different type of indications, but at the same time preserve value for Atara and our shareholders for this potential game changer in the field of MS and autoimmune disease.
Does it answer your question, Tessa?
Absolutely, t hank you so much for taking our question.
Thank you.
Our next question is coming from the line of Phil Nadeau with Cowen and Company. Please proceed with your questions.
Good afternoon, c ongrats on progress, and thanks for taking our questions, a few from us. First on tab-cel, we're curious whether you'd be willing to provide any more detail on what remains to be aligned between Atara and the FDA on comparability. If not, maybe just broadly as we think about allogeneic cell therapy products, what are the key elements of characterizing comparability between one production batch versus another or cells that are manufactured by one group versus another?
Thank you, Phil, for your question. Jakob, do you want to start and I'll follow on?
Yeah, absolutely. In our discussions with the agency about comparability, we're focused on the discussions regarding the pivotal material that we used in the ALLELE study and then the commercial material. In point of fact, there are some very small differences actually between the pivotal material and the commercial material. It's really just refinements that we're making. We believe that we actually have a very strong data package supporting the comparability of the pivotal material to the commercial material. Yes, there are a few refinements that have been made to get this product up to the GMP level for commercialization as well. Again, we think this is manageable and we have a strong case.
Maybe what I could add, Phil, that while at this stage we cannot share specifics of this ongoing dialogue with the FDA, maybe I can give an example of the type of topics that we are discussing with them. That example would be the number of manufactured lots to be included in an allogeneic cell therapy comparability study. I think we shared in the past that we have analyzed for each process version 15 lots per product versions in our comparability studies, which on one hand is much, much more than the typical three lots that one will have to use for comparability studies for small and large molecule type of product. It's less than what autologous CAR-T will do, because for autologous CAR-T, as you know, each patient requires his own unique manufacturing lot.
That's why they have more, as many patients as they have in a study, they have a lot per patient. We are different there, that's the whole purpose, by the way, of allogeneic cell therapy. It is to treat many patients with one manufactured lot. You can have fewer lots being manufactured and you have lower cost of goods and more accessibility and availability of therapies for patients. We believe 15 lots is significant for such allogeneic cell therapy, particularly in the context of a rare disease, that's why we feel strong about this robustness of our data package there. That gives you an example of the type of discussion we have with the FDA to make sure that it applies to tab- cel and also it's in line with what is the fundamentals of allogeneic cell therapy. Does it answer your question, Phil?
Yeah, that's very helpful, t hat's perfect. Second question on the Q2 data cut that you noted would complete module 5, the clinical module. What determines the timing of that data cut? Is there a maximum time elapsed from the data cut to the completion of the filing, or is it some other element that determines when exactly you make that data cut?
AJ?
Yeah and t hanks for the question. I think the data cut timing is really based upon the prior discussions we've had with FDA on the amount of data that they wanted to complete the filing. Remember, they were looking for specific numbers of patients with a specific amount of duration of follow-up. The data cut is timed to ensure we have the right amount of data to complete that filing.
Perfect. Last clinical questions on the mesothelioma program. What do you imagine would be the path to market for 2271? Do you think that what we saw from the initial CAR-Ts in B cell malignancies is reasonable, meaning like a single arm study in a very severe patient population, or w ould you expect something more rigorous?
No, thank you. I think it's a good question. I'll start, and Jakob or AJ, you might want to chime in there. I would say in the CAR-T space, it depends very much on the indication and what's available for that indication there. In advanced mesothelioma, for example, there is a clear medical need with no treatment that is able really to allow for long-term control of the disease in these patients there, or elimination of the disease there. Having a treatment that is having a very impactful effect in terms of objective response rate, in terms of mRECIST in particular, and then having duration of response is what usually allows the FDA to accept that as a pivotal to go to approval. It has to be really this high level of objective response and duration of response.
To move beyond that into situations where there are existing therapies, that is where there might be a need at some stage for the CAR-T field to go into more comparative type of studies. The way we see right now, our first type of clinical work with ATA2271, this is addressing patients that have limited options, and then having high level of objective response rate as well as duration of response means that this could be discussed with the FDA for potential submission there. I don't know whether Jakob or AJ want to add anything to that.
Yeah, I completely agree, Pascal, with the statement. I do think in mesothelioma, there is a treatment paradigm focused obviously on chemotherapy, but we know the checkpoint inhibitors, the PD-1 axis drugs do have activity here. Again, focusing on that unmet need, those patients that really don't have any more treatment options, that is the best path now. As we've also described for 2271, it is a mesothelin antigen-directed CAR-T. It also has 1XX, which we think is going to be a preferred co-stimulatory domain for persistence and activity of that CAR. The other key point here is that we built in PD-1 dominant negative receptor into that CAR-T. You're intrinsically providing an overcoming of the immune suppression that the mesothelioma is providing through PD-L1 tumor expression. The fact that this is built into the cell, we think augments the chances of success here.
I think from a development standpoint, by far the clearest path to rapid approval is to go into a late line, unmet need population, single arm study, response rate, duration of response.
Perfect, t hat's very helpful, and then l ast question is just a housekeeping question on financials. You had about $3.6 million in revenue this quarter from the Bayer collaboration. Was there anything special about the amount of activity you did for Bayer in Q1 or should we assume some similar amount of revenue in all quarters going forward?
It's Utpal, thanks for that question. We have roughly $70 million of deferred revenue on our balance sheet, and it's going to be a bit choppy in terms of how this revenue gets recognized on the P&L. As you start to model it out, it's a level of effort that we're putting into delivering on the commitments to Bayer. This $70-odd million, you should see come through the P&L over the next two to three years. That's what you should be looking for.
That's very helpful. Thank you.
Our next question comes from the line of Salveen Richter with Goldman Sachs. Please proceed with your questions.
Hey, good afternoon. This is Elizabeth on for Salveen. I guess just a broad question here in how you're thinking of allocating resources in the context of expanding the tab-cel program, running the MS program, and then also the emerging mesothelin CAR T program, how all of these are developing in parallel. Thank you.
No, thank you, Elizabeth, for your question. I'll start, and Utpal might want to chime in there. It's an important question because we are moving into not only commercial stage, we expect next year for tab-cel, but of course pivotal development of ATA188, and then further clinical studies with our allogeneic CAR-T portfolio there and pipeline. The way we see it is, for tab-cel is relatively clear that we have decided to partner for Europe, so we are now actively discussing with a number of companies. It's moving very well indeed. The idea will be that we won't have any expenses linked with Europe for tab-cel, because that will be covered by the partnering there.
For the U.S., we have decided to launch ourselves, so we are starting to invest progressively into some activities, and that will progressively go up in time to be ready for the launch, possibly in 2022 there. We believe that we have the approach that makes sense to make it a successful launch in terms of the balance between investment and a return on investment there. We have a very detailed plan put together by Kristin Yarema, our Chief Commercial Officer, for that so t hat's for tab-cel. We are controlling well the situation there. For ATA188, as we say, moving into pivotal studies, especially if we want, as we aim at, to make that a big game changer in the field of MS and autoimmune disease, that's where we believe we'll need a partner to go into that.
That's why we believe a partner in 2022 will allow us to accelerate and expand pivotal study across many indications for ATA188. At the same time, we're also investing in new manufacturing process, which we believe will allow us with certain bioreactor to cover large number of patients with a low cost of goods. That's really a significant investment in ATA188, which is really going to pick up next year. That's going to be aligned with a partnering with a large company there. On the Allo CAR T, on one hand, we have the mesothelin CAR T franchise, for which we have already a partnering in place, and that's being funded really by Bayer there.
For ATA3219, we can fund the next stage of development to be able to go to the clinic next year and to prove that we have here potential best in class in B-cell malignancies. Then, we have a number of other programs that are early stage and might move to IND-enabling studies over the future. In that case, we believe that we will be well-funded to be able to pursue these programs. Clearly today, the key, in terms of resource allocation, is to get to the finish line with tab-cel, have a partner in Europe, launch by ourselves, and create revenues opportunity and profitability progressively in the U.S. On ATA188, which is the second big type of investment we need over the next two years, this is really going to rely on partners.
We are very confident on finding a partner there, because if we are right, everybody will want this type of product, because that's really what everybody's waiting for, something really new, really transformative in MS. This is something in high demand. Does it answer your question?
Yes, that's helpful. Thank you.
Thank you.
Thank you. Our next question comes from the line of Matt Phipps of William Blair. Please proceed with your questions.
Hi, guys. Thanks for taking my question. I'm hoping you can kind of clarify some things with me, because when I go back and look at your January regulatory update press release and your Q4 press release, all the talk of CMC and, you know, module 3 is related to the comparability between non-pivotal study and pivotal study and, you know, there was a lot of discussion on whether this was going to be looked at parallel or, you know, pooled. Now you're saying that it's more an issue between the product used in the pivotal and the intended commercial product. This seems like a much different issue, and I'm wondering if the original issue has been resolved and if this one has just recently come up, or if there are any other details you can give us on that.
Yeah. No, thank you for your question, Matt. Jakob, do you want to start and I'll chime in?
Sure, a bsolutely, so t hanks for the question, Matt. They are really related questions here because the comparability issue of pivotal to commercial, you know, that needs to be solved for the sake of the BLA filing. We're focused on that particular part. Once we have the discussions with the FDA and we've come to agreement around those comparability aspects, they are going to be applied to the same topic when you think about the h istorical to the pivotal, so t his is really all part of the same discussion. We are focusing particularly on pivotal to commercial, because there we're getting all of the information that's going to help inform this other topic of historical to pivotal.
I will add that it was really in two steps, t hat's why the communication has been in two steps, Matt. There was a first step back in the fall where we are discussing with the FDA regarding different aspects of what will be needed for submission. We provided them with data showing, we believe, comparability between historical and pivotal. Since then, we've had, as we say, several Type B meeting and informal calls to discuss about something else, which is a Module 3 CMC. In any Module 3 CMC, one needs to show comparability between pivotal and intended commercial. That's a prerequisite to file a BLA. It was really two steps in terms of the discussion with the FDA, and that's why the communication is evolving now. We are really focusing on that one.
Solving that one, and we believe we are making great progress there, will anyway also answer the other one, because it's about the methodology and the type of data that we have on comparability. It really was two steps, and it's really since January that we have had all these specific interactions as part of a BTD status with the FDA and progress made on this aspect that is essential for the module 3 because you need to have this comparability fully aligned with the FDA to be able to move forward there with the BLA. Does it make sense, Matt?
That helps. I get that it's all related, but I guess back in the fall and early in January when it was talk of non-pivotal versus pivotal, had you yet at that point completed your, I guess, 15 lots of commercial product to show to the FDA? Is that something that you have now recently shown them and they are now questioning the comparability of that to the pivotal study data?
Yes, exactly, i t was in two steps. Okay, first step was, and you may remember when we say last year, back in September, we had a Type B meeting, where we provided comparability data between historical and pivotal. Second step had been since then that we provided them and started to discuss that we had a Type B in January, talking about pivotal to commercial. It was a second set of data, and then we have had a further discussion with them based on their guidance. We've done new analysis and so on, so t hat's the second step of discussion has been based on pivotal to commercial.
Okay. I guess the reason you've done 15 lots of comparability for, I guess that's all commercial product, is because you're seeing higher than expected variability, as you go try to compare this to the pivotal or non-pivotal.
No, there was not a higher variability. The 15 lots has been based on statistical methods there to be able to show equivalence based on value statistical test there between two type of process version there. The 15 lots has been done for historical, for pivotal, for intended commercial there. The 15 is not linked with particular aspect, but statistical power to be able to show equivalence between these different process versions.
Okay. Also, you know, the wording specifically now states, methodologies to assess comparability. I assume this is methodologies with data that you have already generated and not something that has to be done as a new analysis or something like that?
Yeah, I think we provided the FDA with methodology from the point of view of statistical analysis and other type of aspect of that methodology on the data on these manufactured lots with different process versions. The alignment that we are having with the FDA is around these methodologies. Again, I'd like to remind you that we are the first in kind. Nobody else has been coming to the FDA with that type of allogeneic cell therapy. As I said, with the example of sample size, the FDA has to align with us being the first about the number of samples, number of lots that make sense for an allogeneic cell therapy, because nobody else has been to that level with the FDA, and I gave that example that is, for a small molecule or large molecule comparability study, you need three manufactured lots.
For an autologous CAR T, you have to provide as many as you manufacture treating patients, is one lot per patient. If you have a study with 60 patient or 100 patient, that means you have 60 or 100 lots. In allogeneic cell therapy, it's different. We believe 15 is very significant, much higher than the three that is being used with molecules. At the same time, it's something that is powered from a statistical point of view to be able to address the variability inherent to cell therapy.
Okay, and I guess, I think the last question, the wording has also clearly changed from on track to complete a rolling submission by Q3 to now working towards completing a BLA in Q3. No mention of rolling. I assume this is just kind of getting things closer to Q3 in general. Well, you're not going to even do a rolling submission. You'll just submit it all in Q3. Is that right?
We can still have a rolling submission. It's not that we cannot have a rolling submission. It's just then there will be some time where we can hold the submission and then complete the submission with the clinical module. Altogether, we think that we are working towards this module 5. As you know, that's based on the data cut and the analysis in Q3 while we are working on the module 3. It depends when we'll have that alignment with the FDA on comparability so then hat means the module 3 can be finalized. There is nothing in our description of the ADA that says that we cannot do a rolling BLA, just to be clear.
Okay. Thank you.
Our next question is coming from the line of Tony Butler with Roth Capital. Please proceed with your questions.
Yes, thanks a lot, Pascal. Apologies, I was just disconnected a little bit. You may have said this, please forgive me. There are really three questions. One is, Jakob alluded to enrolling sites for ATA188 very rapidly. In clinicaltrials.gov, it lists 17. Is that a fair number or w ould there be more sites to be added? That's question one. Number two, Pascal, you sent up a little bit of a trial balloon on 188 suggesting that there was a great deal of, I think your phrase was large company interest in 188. That implies partnership. I just wanted to know what you were thinking around 188 longer term. The third question involves 2271 or i mportantly, the relationship with Bayer. Is that relationship because they're responsible for filing the IND as well as eventually commercialization, will you all be doing the manufacturing?
I'm just trying to separate church and state there with respect to that program. Thanks very much.
Thank you, Tony, for your three questions. Maybe the first one, AJ, you want to address it on the number of sites?
Sure, a bsolutely, y ou're asking whether we're continuing to enroll more sites or activate more sites, and t he answer is absolutely yes. We've got sites open now in the U.S. and in Australia and w e're continuing to add more U.S. sites. We'll also be opening up Canadian sites over the course of this year as well.
Thank you.
Regarding the ATA188 partnering aspect, the discussion we are having with some companies is really around establishing the type of framework from partnering that will create significant value for the company and our shareholders. At the same time, allow us to extend and accelerate the development of this potentially transformative treatment there. That's the type of thing that we think that clearly, as I trying to explain earlier on, moving into pivotal studies in PMS, in relapsing MS, maybe in some other type of autoimmune disease where you have a link, an association between EBV and the disease such as lupus or RA, that requires some partnering because that's a very significant effort, we believe. Partnering should be done in a way that preserves value for the company and our shareholders. That's the overall framework, and I cannot give you more details about that.
Of course, we are working actively on this type of framework there. Now, your last question, 2271. Maybe to clarify, 2271 at this stage, this is the autologous version. The IND is run by Memorial Sloan Kettering, and we are funding that, and of course, we have access to this. Now, moving forward in that development, there will be a need for someone else to move forward if it goes into further development, and that's the plan to have Bayer as a partner there to move forward for 2271. Meanwhile, as we know, we are working towards the IND for 3271, the allogeneic version, and this one, we are doing the work right now, but Bayer, and that's part of the deal, Bayer will be the company filing the IND.
We believe it could be in Q2, Q3 next year, and then developing the product, and then commercializing the product. At this stage, the work done by Atara is really to support the first human study through Memorial with 2271. At the same time, work on the allogeneic 3271 IND-enabling studies to be able then to provide a partner with the right set of data to move forward towards the IND. Does it answer your question?
Yeah. Thank you. Yes, sir, it does. Thank you very much for your time.
Our next question comes from the line of Ben Burnett with Stifel. Please proceed with your question.
Hey, thanks very much. I just wanted to ask a few questions about commercialization plans for tab-cel, and I guess specifically, what capacity do you expect to be at on approval, just in terms of the size of the cell banks? Then secondly, I guess, is there any unique thing that needs to happen here to certify or onboard hospitals? I know that you guys use the Atara MatchMe delivery process. I'm just curious how easy it is to adapt that to new sites and if there's any certification process like we've seen with some CAR-T programs.
Thank you, Ben, for your question. Kristin, do you want to address that question?
Sure, absolutely, and t hank you for the question. As we said before, we're on track building inventory. We expect at the time of launch and soon thereafter to be able to address about 95% of patient needs with our capacity, our inventory. That's very exciting for us and again, we're well on track with that. In terms of some kind of certification requirements or the model, we're doing a lot of work with institutions right now, really going in and doing research with pharmacy directors and cell labs at an individual level. We are not anticipating that we'll require extensive certification requirements. In fact, that's one of the things that we think is quite exciting about our model.
Okay. Thanks very much for the color. I appreciate it.
Yes, and one thing is important also to clarify there, and maybe Joe might want to comment on that, because the differences between the pivotal process version and the commercial process versions are minimal there. That's why we're confident in terms of comparability, that's why we are also confident in terms of building inventory. Joe, do you want to comment on that?
Absolutely, Pascal. I think, the other aspect of it is just we've seen great process control across all of the process versions supporting commercial and the clinical product. We're seeing that. We're seeing increased yield production. To that point of building that inventory, very confident with what we have already made and released to support pre-commercial inventory. We've seen the same level of process control and manufacturing robustness as we continue to build out that library.
Okay, g ot it. Great, t hank you.
Joe, on the differences between the pivotal and the commercial?
Yes, absolutely. I think they're so minimal. Quite honestly, if a change was made, it was generally made to support the commercial GMP compliance requirements to support a BLA. I'll give you an example. We moved the manufacturing site for our EBV viral reagent from a CMO to our own facility in Thousand Oaks. We did that for two reasons. One, better control of our supply, and then most importantly, to ensure that we can meet the commercial GMP compliance requirements in support of the BLA from that facility. Again, minimal changes, and generally if a change was made, it was made to support the BLA success.
Thank you, Joe.
Thank you. Our next question comes from the line of Yigal Nochomovitz with Citi. Please proceed with your question.
Hi, this is Carly on for Yigal. Thanks very much for taking our questions. We had a couple on the CAR T pipeline, specifically on ATA3219, the CD19 program. We're just curious if you had considered incorporating the PD-1 dominant negative receptor into the CD19 program as a potential strategy for boosting persistence. Obviously, it's incorporated into your mesothelin program, so w e were just wondering if you could kind of expand on the rationale for including in the mesothelin CAR Ts, but not for CD19.
Thank you again for your question. Jakob, do you want to address that one?
Yeah. Thanks for that, Carly. In terms of a liquid tumor-targeting product like 3219, it makes sense, obviously, for the binder to be against CD19 as we target these B cells. It also makes sense for 1XX to be in there as we think this is a potentially best-in-class co-stimulatory molecule. The PD-1 DNR is not as useful in the context of liquid tumors, because if you think about the mechanism of immune suppression that occurs in solid tumors, there's the creation of the PD-L1 protein by the tumor that prevents the T cells from really having their effect against solid tumors. That's really not an effect that you find in liquid tumors. There's really not a good need to put the PD-1 DNR into the 3219 specifically because it is targeting B cells that express CD19 in this regard.
We do think the other aspect about 3219 that's so compelling to us is the fact that we're using our allogeneic EBV specific T cell, because what in essence you have is you've got a T cell, a CAR-T cell that will target CD19 on the B cell malignant cells. The EBV specificity, the native EBV TCR that is in these allo T cells, is one that's actually complementary in this setting. You don't need to delete that T cell receptor with something like CRISPR-Cas9 and so forth. It actually leaves these allogeneic T cells more intact by leaving the native TCR in place, which is specific for EBV. We think that the performance and part of the reason why we think 3219 could be best in class is not only because of the 1XX, but also because of the allo EBV T cell specificity of those cells.
Got it, t hat's really helpful, and I guess just sticking with 3219, as you start to think about sort of the initial clinical development plan, can you share any preliminary thoughts on the phase I trial design, particularly regarding types of B-cell malignancies you plan to enroll, whether you would plan to study 3219 in patients who had previously been treated with a CD19 targeted therapy, and any early thoughts you have on lymphodepletion would be helpful. Thank you.
Yeah. Jakob, do you want to start with that?
Yeah, I can start for sure. We will do obviously a classic dose escalation and expansion study, that phase I. We did, as we announced last year, have a good pre-IND meeting with the agency that was very successful last year. We had some early discussions around the phase I clinical trial design, but we have not per se spoken about the details, and it's still an area of refinement that we're working on now. Certainly, CD19 expressing B-cell malignancies will be the target there, and we think there are some very interesting opportunities, again, because of the 3219 molecule or product, where we think there's going to be better persistence here. Because it's allogeneic, there are some other things that you can consider, including potentially redosing of patients as well.
There is a lot of flexibility with that program, and we're going to refine the clinical trial design in the coming months.
I think the other aspect maybe to add on that is so far, whether it's autologous CD19 CAR-T or first kind of initial data with lack of durability proven so far of other allogeneic technologies on CD19, the level of response, if you look at DLBCL, really, not follicular, which is different. The level of response has been more around the 40% in terms of long-term response, long-term CR, because here you need CR in this type of patients there. We believe there is still room to have a best in class with higher level of response. At the same time, durability of response, because the intent is to really have long-term durability of response with a curative intent for this type of product and then, o f course, better safety than the autologous. All of these aspects where we think our approach might bring some interesting data.
We need, of course, to go to the clinic there. From the way we've built the product, we think that we could address this medical need in terms of response rate, safety, and durability of response. Does it answer your question, Carly?
Yes, it does, a ppreciate all the detail. Thank you for taking the questions again.
Thank you.
Thank you. Thank you for joining the Atara Biotherapeutics First Quarter 2021 Financial Results Conference Call. You may now disconnect.