Atara Biotherapeutics Inc (ATRA) 2020 Q3 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Atara Biotherapeutics Q3 2020 Financial Results Call. (Operator Instructions)

I would now like to hand the conference over to your speaker today, Eric Hyllengren, VP of Investor Relations and Finance of Atara Therapeutics. Thank you. Please go ahead, sir.

Thank you, operator. Good afternoon, everyone, and welcome to Atara's Third Quarter 2020 Conference Call. 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.

Earlier today, we issued a press release announcing our third quarter 2020 financial results and operational progress. This press release and an updated investor presentation are available in the Investor and Media section at atarabio.com.

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 Kristin Yarema, Chief Commercial Officer. We will begin with prepared comments from Pascal and Jakob and 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. During the third quarter of 2020, we continue to make excellent progress in delivering on our strategic priorities and advancing of 3 areas of focus: tab-cel, ATA188 in multiple sclerosis and our emerging CAR-T portfolio. We are on track to finish the year strong, meeting each external milestones set to date while progressing on our mission to bring transformative T cell immunotherapies to patients with serious diseases. I would like to thank very much the Atara staff who have worked so hard to deliver on expectations despite the COVID-19 pandemic.

Very significantly, we completed an interim analysis for the tab-cel pivotal 302 study or ALLELE study in the third quarter, achieving a 50% objective response rate by independent oncologic and radiographic review. This objective response rate is consistent with previously published investigator-assessed data, and the tab-cel safety profile in ALLELE is also consistent with previously published data with no new safety signals.

Following these encouraging pivotal interim analysis data for tab-cel in EBV-positive PTLD and very productive interactions with regulatory authorities, we are now preparing for tab-cel regulatory submissions and then potential approval and launch. We were particularly pleased to gain clarity on the regulatory package with FDA, notably that we can initiate a rolling submission and that we can complete the BLA filing with the ALLELE study's currently enrolled patients with at least 6 months of follow-up for durability of response.

We plan to initiate the rolling BLA submission of tab-cel for EBV-positive PTLD by the end of 2020, and we expect to finalize the BLA submission in Q3 2021. We are also on track to submit an EU marketing authorization application for patients with EBV-positive PTLD in the second half of 2021. Jakob will give you more details about these regulatory updates in a moment.

Meanwhile, we are near completion of testing the manufacturing lots that support our commercial validation of our scaled-up process, and we are investing in building the commercial inventory needed for launch. We believe that tab-cel has the potential to transform the treatment of EBV-positive PTLD and offers a compelling value proposition for patients and the health care system. Indeed EBV-positive PTLD is an aggressive, often deadly cancer with no approved therapy. The median survival for HCT and SOT patients with PTLD who are relapsing or are refractory after first-line therapy is only 2 to 3 months. With tab-cel, the survival rate has been shown in prior studies to be over 80% at 2 years among responders, with few treatment-related serious adverse events. In addition, we have been able to deliver tab-cel to U.S. clinical trial patients within 3 days from our inventory and with a relatively low burden of administration on the patients and treatment centers.

In terms of potential label expansion for tab-cel, we initiated the tab-cel Phase II multi-cohort study in Q3 2020 with the goal of expanding the potential label in PTLD and closely related EBV-driven cancers. I would like to specifically highlight tab-cel's potential in additional immunodeficiency-associated lymphoproliferative diseases beyond PTLD given the high unmet medical need for a significant number of such immunocompromised patients, and our new positive clinical data for tab-cel presented at ESMO.

I would like now to transition to our multiple sclerosis program, ATA188. We are very excited about the potential for ATA188 to become a transformative therapy for MS patients, bringing clinical benefits not achieved so far with existing therapies.

As a reminder, data presented at the joint ACTRIMS-ECTRIMS meeting held in September 2020 showed that patients with progressive MS who achieved sustained disability improvements, or SDI, with ATA188 therapy at any time point maintained it at all future time points, and a higher proportion of patients showed SDI with increasing dose. We will continue to present additional data from our open-label extension periodically over the next 12 months, with the next readout of such additional data at the European Charcot Foundation 28th Annual Meeting, to be held on November 15, 2020.

Additionally, we are increasing our investment to support ATA188 in translational research, manufacturing process improvements and clinical development. In particular, we are advancing as rapidly as possible the enrollment of patients in the double-blind, randomized, placebo-controlled trial, which aims at confirming the transformative impact of this new therapy in MS.

Switching now to CAR T. We believe that we have an exciting portfolio of innovative and differentiated CAR T programs. These programs are based on our EBV T-cell platform and our ability to leverage new technologies like 1XX and PD1 DNR to improve efficacy, persistence and durability of response, hence addressing limitations of autologous and other allogeneic CAR T. Jakob will detail in a moment the progress we are making in developing these exciting and competitive programs.

With regard to our cash position and runway, we ended the third quarter of 2020 with $327.2 million in cash, cash equivalents and short-term investments, which we believe are sufficient to fund planned operations into 2022.

Atara's unique allogeneic EBV T-cell platform has the ability to deliver off-the-shelf therapeutics with potentially transformative efficacy and safety profiles and to produce them at scale, meeting the needs of large patient populations. We believe strongly that this differentiates us from our peers.

As we are rapidly progressing on creating value across our 3 strategic priorities, I'd like to conclude by expressing sincere thanks to the patients, caregivers, collaborators and staff at Atara. We are all committed to delivering on our corporate goals and creating shareholder value.

I will now turn the call over to Jakob. Jakob?

Thank you Pascal. This quarter, we have made significant progress advancing tab-cel in Phase III for EBV-positive PTLD, for which we have obtained breakthrough designation in the United States and PRIME designation in Europe. We conducted the interim analysis and had very productive interactions with regulatory authorities and gained clarity on the regulatory package in both regions.

The IA for the tab-cel ALLELE study was conducted in the third quarter. As Pascal noted, we achieved a 50% objective response rate with independent oncologic and radiographic review in patients with EBV-positive PTLD following either HCT or SOT that had reached at least 6 months follow-up after initial response. This overall response rate is consistent with previously published investigator-assessed ORR data. The tab-cel safety profile in ALLELE in the interim analysis is also consistent with previously published data with no new safety signals.

During a recent Type B meeting, we presented a comprehensive data package of tab-cel clinical data to the FDA. This clinical package included the ALLELE interim analysis, Phase I and Phase II studies with Memorial Sloan Kettering, the Atara Phase II EAP 201 study and real-world experiences from single patient use data. We shared extensive efficacy and safety data with the agency. After productive discussions with the FDA, we now have clarity and alignment on key aspects of the regulatory package to support the BLA for tab-cel in EBV-positive PTLD including the points that: number one, a regulatory submission is acceptable for the BLA; additionally, we had completed the BLA submission with the current number of patients enrolled in the study with follow-up for duration of response of at least 6 months; and finally, the FDA will consider as supportive data to the pivotal study the following: the MSK studies, the 201 study and the real-world experience in the BLA clinical module.

In a separate recent Type B meeting with the FDA we also had a productive discussion regarding our manufacturing approach for tab-cel and the CMC data needed in the BLA submission. We remain on track to initiate a rolling BLA submission for patients with EBV-positive PTLD by the end of 2020, and we will continue to engage with the FDA as part of our rolling BLA and BTD status and expect to finalize the BLA submission in Q3 2021 after having followed for at least 6 months the responders amongst already enrolled patients. Following discussions with the PRIME team and after EMA approval of the Pediatric Investigation Plan, which we anticipate will occur in December of this year, we expect to remain on track to submit an EU marketing authorization application for patients with relapsed/refractory EBV-positive PTLD in the second half of 2021. Finally, data from the pivotal ALLELE study will be presented at an appropriate forum in 2021.

Furthermore, regarding tab-cel, we initiated the tab-cel Phase II multi-cohort study in the third quarter and expect to enroll the first patient in the fourth quarter of this year. This study is being conducted concurrently in the U.S. and the EU in order to enrich the evidence base, with the goal of expanding the potential label for tab-cel, a therapy believed to provide significant value for those with other severe and life-threatening EBV-driven diseases.

Data demonstrating tab-cel was well-tolerated and showed encouraging clinical activity in patients with EBV-positive acquired and primary immunodeficiency lymphoproliferative diseases were featured in an e-poster at the European Society for Medical Oncology 2020 Virtual Congress held in September of this year. Specifically, in patients where previous treatments have failed, the objective response rate was 33.3% in AID-LPD and 37.5% in PID-LPD groups. We also saw several patients with complete responses to tab-cel. Tab-cel was generally well tolerated with a favorable safety profile consistent with previously published clinical studies.

Patients with PID-LPD and AID-LPD have substantial unmet need, and there are no approved therapies for these diseases. Those who relapse or fail to respond to initial chemotherapy have poor prognoses. In PID-LPD especially, there is a need for effective chemotherapy-free options because these patients have an underlying genetic immunodeficiency and often cannot tolerate standard doses of chemotherapy due to the risk of life-threatening infections. The multi-cohort study will evaluate both treatment-naive and previously treated patients in 6 patient populations with significant unmet need, including within immunodeficiency-associated LPDs, 2 cohorts addressing front-line EBV-positive PTLD patients as well as 2 cohorts addressing EBV-positive LPDs arising out of primary or acquired immunodeficiencies, including AID-LPD and PID-LPD. We look forward to sharing more on this study in upcoming conference calls.

Turning now to our exciting program ATA188 for multiple sclerosis. As most of us know, progressive MS patients remain underserved with the current treatment options. Unfortunately, a continual decline of their disease is expected in progressive MS. The current treatment options offer a modest efficacy benefit, at best, only delay progression -- only delaying progression by a few months. We believe there is a tremendous opportunity to develop a transformative therapy to help these patients in need. We have seen early but encouraging data with ATA188.

Recall that we presented important 12-month Phase Ia data for ATA188 at the joint ACTRIMS-ECTRIMS meeting held in September of 2020. These data demonstrated that ATA188 was well-tolerated across all 4 dose cohorts. No dose-limiting toxicities and no fatal adverse events have been reported. The safety profile has remained consistent with previously reported data. Importantly, a meaningful number of patients across all 4 dose cohorts achieved sustained disability improvements, or SDI, with a greater proportion demonstrating SDI at higher doses, particularly 42% of patients had SDI in the 2 highest dose cohorts, namely cohorts 3 and 4. And once patients achieved SDI at any time point, they maintained it at all future time points. Sustained disability improvement is rare in this patient population and the fact that we have a number of progressive MS patients with this evidence of benefit is very encouraging.

Data from the open-label extension, or OLE, part of the study, with redosing at 12 months show that the 3 patients enrolled in the OLE that had SDI at 12 months, all maintained SDI at 15 months, including one patient evaluated at 15 months and 18 months who maintained SDI at both time points. A fourth patient achieved SDI during the OLE at 24 months. We will present additional data on larger numbers of OLE patients periodically over the next 12 months.

We also presented at ACTRIMS-ECTRIMS preclinical translational data that further support the proposed mechanism of action of ATA188, which is to target EBV-infected B cells and plasma cells in multiple sclerosis. These analyses of the ATA188 T cells reveals that there is a high specificity of these T cells defined by their T cell receptors to EBV antigens known to be expressed in multiple sclerosis.

Looking ahead, we will present an e-poster with additional data from the OLE and all 4 cohorts at the European Charcot Foundation 28th Annual Meeting, to be held very soon, November 15 to 19, 2020.

With respect to the double-blind, randomized, placebo-controlled trial, we enrolled the first patient in June of 2020, and the study enrollment is progressing well. Given encouraging clinical results to date in the ATA188 studies and the significant unmet medical need in progressive MS, we are now increasing our investment in the ATA188 program. We are expanding the size of the RCT to at least 64 patients, changing the primary endpoint of the study to disability improvement and maintaining biological endpoints to create more opportunity to generate meaningful clinical data and deliver value. The design allows for the addition of the cohort 4 dose if desired. In addition to measuring disability progression, the study will evaluate other facets of disease, including: cognition; outpatient ambulatory activity level and fatigue; biomarkers in blood and CSF; and MRI imaging. We have submitted material to the FDA that includes the Phase Ia data, the planned updated design of the RCT study and potential opportunities for expedited development of ATA188 for MS patients. We look forward to receiving the agency feedback by the end of this year.

I'd now like to provide an update to our CAR T portfolio. As Pascal mentioned, we continue to make significant progress on all fronts. As we noted last quarter, our collaborators at Memorial Sloan Kettering had submitted an IND application to the FDA for our next generation mesothelin-targeted autologous CAR T immunotherapy, called ATA2271. The clinical study has been initiated at MSK, and they are on track to enroll the first patient in the Phase I study in the next few months.

In addition, we are making progress through IND-enabling studies with our allogeneic mesothelin CAR T program called ATA3271, which utilizes the 1XX and the PD1 DNR technologies, leveraging our differentiated EBV T-cell platform. This 1XX and PD1 DNR construct is associated with less cell exhaustion, improvements in functional persistence, serial cell killing and in vivo efficacy which was maintained through multiple tumor rechallenges when compared with first-generation CD28/CD3z-based mesothelin CAR.

New preclinical data show that 3271 demonstrates potent anti-tumor activity, persistence and significant survival benefit without evidence of allo cytotoxicity, both in vitro and in vivo, suggesting that allogeneic mesothelin CAR engineered EBV T cells are a promising approach for the treatment of mesothelin-positive cancers. These data will be presented at the Society for Immunotherapy of Cancer, or SITC, 35th Anniversary Annual Meeting between November 11 and 14 of this year.

Now moving on to ATA3219, our potent next-generation off-the-shelf allogeneic CD19 CAR T utilizing the 1XX technology without the need for TCR editing. We conducted a collaborative and successful pre-IND meeting with the FDA in October of this year and received feedback to guide the IND filing. IND-enabling studies are progressing with a package expected to be filed in 2021. An abstract detailing ATA3219 preclinical data was accepted for presentation at the 62nd Annual Society of Hematology (sic) [American Society of Hematology], or ASH, Annual Meeting and Exposition being held virtually from December 5 through 8 of this year. These preclinical data of ATA3219 demonstrate persistence, polyfunctional phenotype and efficient targeting of CD19-expressing tumor cells, both in vitro and in vivo, without evidence of allo cytotoxicity in vivo. This will be the first abstract presented on ATA3219.

Finally, I would like to extend my sincere thank you to our staff, collaborators, patients and caregivers. We have accomplished much in this quarter thanks to you, and I look forward to providing updates on our continued progress in the near future.

I'll now turn the call back to the operator to begin the Q&A portion of the call. Operator?

(Operator Instructions) Our first question comes from the line of John Newman with Canaccord.

Congrats on the very interesting data here. I wasn't expecting an interim this quickly, but this is very good. Curious if you could talk at all about the breakout between patients receiving tab-cel after stem cell transplant versus patients receiving tab-cel after solid organ transplant? Also curious, I know in the earlier studies, there were, I think, very few, if any, patients that experienced relapse after responsive tests. So I wondered if you could comment as to what you're seeing there.

Thank you, John, for your questions. Jakob, do you want to take these 2 questions, 1 on the HCT versus SOT, any differences there?

Yes, absolutely. So thank you for the question, John. We have enrolled in the ALLELE study both patients with HCT and SOT previously, and they have received prior therapy as per the protocol characteristics. We have not disclosed the breakdown of the exact number of HCT or SOT patients, but they are both reflected and enrolled in the study thus far. And we have shared data with the agency of both these HCT and SOT patients from the ALLELE study as well as, as I mentioned, the historical data from the Memorial Sloan Kettering studies, the expanded access, the 201 study and the SPU, and that comprehensive data package includes both HCT patients as well as SOT patients.

And I think I will add that in the previous data, the prior studies that we presented, there were indeed some differences, but we believe these differences in response rates were not so much linked with differences in the disease itself but more in specific patients because the disease is the same. That's why we are really aiming at considering that together for the BLA filing. Of course, the FDA has agreed this can be done and also that it will require demonstrating sufficient benefit in the combined population as well as in each cohort separately, and that's the type of data that we'll bring forward to the FDA.

Now to the second question related to any type of relapse after response to tab-cel, do you want to address that Jakob?

Certainly. So we are, of course, following patients on the ALLELE study for any concerns around relapse. And we're following for duration of response as well. And we can turn once again to the historical experience with tab-cel, where, as Pascal was making reference in the historical data, we see a response rate by investigator's assessment of 50% to 80%, either HCT or SOT. And we actually see the long-term durability of response to be quite profound, where we see patients at 2 years with survival follow-up that we see on the order of over 80% of patients alive at 2 years. That's in our historical experience. We are certainly going to continue to follow these patients who are on the ALLELE study, but we feel good about the response rate and the durability of response that these very sick patients gain from tab-cel.

And point of reference, and this was mentioned by Pascal, the survival outcome for HCT and SOT patients with EBV-positive PTLD after receiving previous therapy is on the order of 2 to 3 months. So the fact that we see the numbers that we see in our historical data, we think, is very promising.

And our next question comes from the line of Salim Syed with Mizuho.

Great. Appreciate the color, and congrats on the progress. A few for me, if I can. One, just following up on the duration of response for tab-cel. Was the 6 months follow-up duration, was that something that the FDA recently communicated to you? Or was this something that was always that, that was the specific number and only now you're disclosing it? Or was it something that they looked at in the current data center like, okay, 6 months is kind of the appropriate time line here?

Second question, just on the ATA188 program. Just similarly, on the change in the primary endpoint into disability improvement, was that done in concert with the FDA? Just a simple yes/no there, I guess, is fine. And then just lastly, on the OLE data that we're going to be getting at Charcot, is that just going to be, again, all patients who are past the 12-month marker? Or what exactly is the cut-off data that we'll be getting?

Thank you. I'll start to address the first question, and Jakob can chime in, and AJ will address the ATA188 question. So clearly, the 6 months duration of response follow-up that is being asked by the FDA is not surprising. That's something we had discussed already with them in the past. And that's why the data we're presenting here from the IA, this 50% objective response rate, is really in that patient that have the 6 months follow-up following response, okay? So that's the 50%.

Now what the FDA is asking now is to have all the patients that have been enrolled so far in ALLELE that we discussed with them in October when we had that Type B meeting to be then followed for 6 months following response. But there is not any surprise about the duration of follow-up that is required from the FDA.

Jakob, anything to add to that?

Yes. I think you're absolutely right, Pascal. I think it's a very common request from the agency when you have response rate data for a drug that 6 months duration of response is desired. And so as Pascal mentioned, we have this feedback. We've built it into our statistical analysis plan for the ALLELE study, and we're very much on track in this regard.

AJ, do you want to address the question on ATA188 and the change in primary endpoint there?

Sure. So thanks, Salim. With regard to the primary endpoint, we have changed the primary endpoint in the protocol. And we've actually submitted that protocol as part of the communication with FDA, and I think, as per Jakob's comments a little bit earlier, we do expect a response from them this year on their view on all of the changes we made to the protocol. But in terms of making that endpoint change, we've already made the endpoint change.

And then there was a question on OLE at Charcot?

Sure. And for the OLE data, yes, you're going to see -- basically the thing that you will show is just an update on all the patients that we presented, of course, previously as well as some of the additional patients that enrolled into the open-label extension since the last time. So there'll be a significant increase in the number of patients on which we report.

And our next question comes from the line of Jonathan Miller with Evercore ISI.

Congrats on all the progress. I'd like to focus in on tab-cel in the multi-cohort study. And maybe you could just remind us the timing of some of those different cohorts within that study and how you would plan to report this cohort. Then I assume that the pan-EBV-positive indication you teased as a possibility in the past might require additional indications beyond the Phase II. Or do you think it would be possible to talk to the FDA about that kind of genotypically based indication with those data sets that you have? And then just returning briefly to PTLD, do you expect the FDA to differentiate between HCT and SOT in the label given your prior experience with those 2 indications and what you see in ALLELE? Or will those be really wrapped up together?

Thank you, Jon. AJ, you might want to address the first questions on the multi-cohort's timing, the different cohorts, and then Jakob will address the next 2.

Sure. From the timing perspective, we've opened up the AID-LPD and PID-LPD cohorts as well as the cohorts on EBV-positive leiomyosarcoma. The ones that we're holding off on just a bit from a timing perspective are the PTLD cohorts. Though they don't directly compete with the 302 study, there's always a theoretical possibility. So we want to hold off on those until we're complete on the 302, but the other cohorts are open.

Yes. And I think the data we expect to come first will be from the 2 cohorts with more patients, by definition, addressable there, which are the AID and PID. And that's the data we believe could come as early as 2023. Jakob, do you want to address the questions on how we want to discuss with the FDA a potential pan-EBV indication or indication for all EBV-related cancers?

Absolutely. So thanks, Jon, for the question. So we believe in the multi-cohort study that each one of the distinct populations, each of the cohorts, represents a distinct opportunity for a regulatory filing. So that's the first stage. But we also recognize that with the eventual approval of tab-cel in PTLD and then adding on the additional cohorts that there's this mounting of information that if you have an EBV-positive cancer, that tab-cel provides benefit for you. So that certainly provides the opportunity for a tumor-agnostic label, where, again, we have a diagnostic test to show EBV positivity. And then we have a specific therapy, namely allogeneic EBV T cells that can target that particular abnormality in the tumors that we think this is right for a tumor-agnostic indication.

And certainly, as we generate data, not unlike we did with the ALLELE study, we're going to look for opportunity to share the data with the FDA and to engage upon potential regulatory filings, either with individual cohorts or as the data mounts with a more tumor-agnostic label.

And to your last question, I think as I said earlier, HCT and SOT cohorts will be considered together for the BLA filing. The FDA has agreed that this can be done and will also ask for sufficient benefit in the combined population as well as in each cohort separately. This was, by the way, also the indication for BTD status, to look at that in a combined way there. So meanwhile, we will be continuing to have discussions with the FDA regarding how this patient population will be addressed in our potential label, and we'll communicate that feedback at an appropriate time. Does it answer your question?

Yes, absolutely.

Our next question comes from Ben Burnett with Stifel.

Great. And I'll add my congrats to the data as well. Just first question on just kind of the safety profile, anything you can give on that, just given that this is a partially HLA match product. Did you see anything that was surprising in terms of graft versus host disease or notable there? And then also just given that this is a T cell product, did you see anything in terms of CRS or neurotox, we've seen in certain CAR T studies? And then if you don't mind, I have one follow-up.

Yes. Jakob, do you want to take that one?

Yes, certainly. So Ben, thanks for that question. This is, as noted, a partial HLA match product. And we've spoken about the potency and the efficacy that we see there, but that comes actually with a very good safety profile. We have not seen any CRS with this therapeutic. We have not seen any neurotoxicity. We have not seen any treatment-related mortality. And recall that this is actually a therapeutic which has quite a lot of clinical experience between obviously the ALLELE pivotal data that we're just describing for you today, but also the Memorial Sloan Kettering Phase II experience, our Phase II trial, the 201 trial, as well as the single patient use and expanded access experience. So we have quite a lot, a large safety experience. And I think we can say throughout that, that we really have a very acceptable safety profile, an excellent safety profile. And to your question, we don't see any of those serious effects, either CRS, neurotoxicity or treatment-related mortality. And recall that this is an off-the-shelf therapy where we can deliver this to patients within 3 days. So we think that this is quite meaningful for patients.

As well as -- I will insist on the fact that if you think about the platform of this partially HLA match therapy, the tab-cell or ATA188, altogether with our academic partners, ourselves now at Atara, we have treated several hundred patients, about 300, we believe, in total there since the beginning. And that means that we have a very strong safety database there in terms -- a very comprehensive safety database in terms of all the patients that have been treated with these partially HLA-matched T cell therapy. So we feel confident about having a very good profile to be discussed with the FDA once we initiate the BLA.

And maybe just one final point, just to underscore that in the pivotal ALLELE data set, we did not see any new safety signals either. So that also increases our confidence.

Okay. Okay. Fantastic. That's super helpful. And if I could just ask one about your experience with the manufacturing and supplying tab-cel in the ALLELE Phase III study, a multi-center study. So I guess what was the time lines for delivering tab-cel to patients? I guess you have an average number there. And were there any patients who didn't get product because of a proper HLA match?

Thank you for your question. The answer is no. But maybe, Joe, you want to add a few color to that in terms of our experience in delivering tab-cel within a few days to patients?

Thanks, Pascal. And Ben, thanks for the question. Yes, our delivery response times and delivery to patients have stayed relatively consistent prior to COVID and during COVID, which I think is quite a testament to our overall platform architecture and our ability to get tab-cel to patients quickly but easily within 3 days domestically. And we have dropped no shipments whatsoever during that period of time. And quite honestly, we've actually seen performance even get better recently. So from that perspective, very consistent, quite a validation for our delivery portion of our supply chain and quite a compliment to the efforts made by the supply chain team here at Atara and the clinical sites that we support.

Understood. Okay. And Pascal, if I understood you correctly, you said there were no patients who didn't get product because of improper HLA match?

I think we have been able to enroll all the patients with a proper matching there, that we could deliver to them. As you know, in terms of the inventory we're building, our plan at the time of commercial stage is to cover over 95% of the total patient population with our cell lines for tab-cel.

And our next question comes from the line of Marc Frahm with Cowen.

Congrats on the data this evening. Maybe first since the interim was taken in August, 6 months of follow-up would imply that you'll have that in, roughly, February. I guess is that the rate-limiting step in the turnaround to Q3 completing the BLA, is just the time you need to turn around the 6-month follow-up into a submission? Or are there other things that are also limiting how quickly you can complete the rolling BLA?

Yes. I'll start. And Jakob, you might want to chime in there. What's happening that in the Q3, when we did the IA, we had a certain number of patients with that 6 months follow-up response there. That's the group of patients for which we present the 50% of our response rate, our objective response rate. Now at the time of the discussion, the Type B meeting with the FDA that was in October, we had other patients that have been enrolled. And what the FDA is asking is basically to have the duration of follow-up for the response for these patients as well. So that's why you then end up into this Q3'21 completion of the submission.

Jakob, anything to add?

Yes. And I just want to underscore also the rigor of the process. So we mentioned the 50% response rate of the interim data. And that was by IORA, so independent oncologic and radiographic assessment. So there is this additional step where we provide this data to an independent authority that analyzes not only the images but also the patient histories and cases, and then we get this independent assessment, which is really apart from Atara. And that additional step takes a little while.

So again, as we look at the overall span of the BLA filing, as we said, we're initiating the BLA here, is our plan in December, and then we'll have the data cut, then we'll do the full analysis with the independent authority. And then we'll analyze the data and put it all together in the clinical module. Meanwhile, we're also putting the other aspects of the following together, the CMC module and these other things. So that's one of the advantages of the rolling BLA that we're also going to be undertaking, is that we can take the systematic approach with the rolling BLA and also because of our BTD status to really ensure a complete, robust and successful filing.

Great. That's very helpful. And then in your prepared comments, you mentioned having a second meeting with the FDA around the CMC issues. Do you have complete agreement now on exactly what assays you need to submit for things like comparability? Or is there still some discussion with the FDA to have there? And then if you do have the full agreement, do you have all that data in hand already? Or are there still tests that need to be run?

Yes. I'll start, and Jakob you may chime in there. I think we have had good progress in discussing the CMC module, and we're making good progress there. At the same time, and Joe might want to chime in as well. We are testing these batches, the slots that we are making for the commercial stage. And we just need to finalize that. We're posting very well to be able to finalize the CMC model. But we had clarity already from the FDA, and we continue to discuss with them as part of the BTD and as part of our rolling submission. Jakob, to start with. And Joe, if you have anything to add, but Jakob, to start.

Yes. I think that's really true. And I mean this is, and Joe can articulate further, but this is an ongoing dialogue that we have been having, Joe and a number of experts here at Atara with the FDA around CMC. And I think we've made a lot of progress on the understanding of what needs to be in the BLA. So I think we're feeling quite good about the progress, but Joe, you can probably speak more specifically to the assays that was the nature of the question that Marc asked.

You bet. Thanks for the question, Marc. Yes, as Jakob mentioned and Pascal, ever since I've been here 3.5 years, we've really been in a very good collaboration with the FDA about developing and validating the assays to demonstrate tab-cel's potency and how the product works in accordance with its stated mechanism of action. So from that perspective, there's been outstanding connection with them. They're aware of everything that we have done to support that. In addition, a big part, as you well know, module 3, is the process performance qualification aspect. We've completed all activities associated with that, including test, and we're clearly just finishing up the final report that will be a part of the submission.

So from our perspective, good representation of our collaborative approach with the FDA, testing looks very solid. And we think we have a very strong package that we're confident will land us in the right position.

And our next question comes from the line of Yigal Nochomovitz with Citi.

This is Samantha on for Yigal. And I'll add my congrats on the data. Just first, are you able to tell us how many patients were included in the interim analysis?

Jakob?

So at this stage, we are not commenting on the number of patients that were in the interim analysis. We, as mentioned, are in discussions with the FDA, and we have enrolled a number of patients currently that will form the basis of the clinical data in that BLA filing, but we are not currently commenting on the sample size.

Okay. Understood. And then presumably, you're continuing to enroll because you haven't enrolled all 66 patients. I understand you're not going to have 6 months durability data for all of those patients. But are you considering including those incremental patients in at least the ORR analysis for the BLA?

Jakob?

Yes. Thanks for the question. So yes, we continue to enroll patients in the ALLELE study. But as I mentioned, this is despite the fact that we have enrolled the number of patients required to provide the necessary number of patients for the BLA filing, and we'll get the durability of response to complete the BLA. But we think that the additional patients enroll give us further data during the expected BLA and market authorization review process that further supports subsequent discussions with payers as well. And we also will continue to receive demand for tab-cel through our EAP, which can lead to opening of new sites as well. So we think the right thing to do is to continue to enroll patients on the study and the EAP to provide that for patients. But as mentioned, we have enrolled the number of patients required for the BLA submission.

Yes. So just to be clear, again, there, we don't need to enroll more patients to finalize our BLA submission, the clinical model. We just need to have a follow-up for the currently enrolled patient. But we've decided to continue the enrollment, as has been said, to expand the database for other use and also to make sure that we can offer access to patients in need.

Okay. Understood. That's helpful. And then just switching to ATA2271, the Phase I trial that's going to enroll the first patient this quarter. Can you just give a little bit more detail on that Phase I trial? Are you targeting a specific tumor type? Or will it be all-comers that express mesothelin? And is there a certain cut-off for mesothelin expression that is required for study entry?

Yes. This is an advanced mesothelioma trial. And Jakob, do you want to comment from specific cut-off on mesothelioma entry?

Yes, absolutely. So this is really utilizing the pathology lab tests for mesothelin at Memorial Sloan Kettering. So this is an IHC, immunohistochemistry, test that's being utilized. And so they're using standard path lab IHC metrics for that inclusion criteria.

Okay. And then just last one for me. Is there any reason to believe that 2271, would it work in other tumors that express mesothelin? Or do you expect this to be targeted specifically to mesothelioma?

Yes. This is Jakob again. So we do believe that ATA2271 and the allogeneic one to follow, 3271, would certainly have potential in a number of other solid tumor types. And so we certainly are initiating in mesothelioma, but you can think of a number of other solid tumors, including pancreatic cancer, non-small cell lung cancer, ovarian cancer and a number of others where mesothelin is overexpressed on those tumors, where this type of potent CAR-T therapy could provide benefit for patients. So our intention is certainly to explore both of these cell products in wider populations beyond simply mesothelioma.

(Operator Instructions) Our next question comes from Matt Phipps with William Blair.

Congrats on the interim and FDA clearance here. I do have one question. In the 10-Q just filed, there's an added line saying that based on an interim, a post-marketing requirement may be, I guess, added. So is that based on any feedback from the FDA on any post-marketing requirements after this interim analysis or maybe EMA?

Thank you for that, Matt. No, I think it's not based on the specific discussion that we have on that. It's just a typical type of situation that when you have a submission based on some interim data there. And then there might be some additional ask in terms of commitments. So I wanted to make sure that this is clear, but there is no specific discussion about that, that took place either with the EMA or the FDA.

Great, Pascal. I guess a follow-up on the mesothelin CAR. I know the, I guess, original academic version that's being conducted in MSK also started to look at IV delivery. I don't believe there's been any presentation of that data. I know you guys are starting out with an intrapleural infusion. But just curious, I guess, if we'll get any update from an IV delivery of the first-gen mesothelin CAR, or if you guys plan to eventually look at IV as well.

I think what's happening is that the first-gen is an academic program, as you know. It's not an Atara program. That's one that is being pursued by MSK, and they will probably want to continue to make some presentation of data when the data are maturing there at some stage. But this is not an Atara program. However, for 2271, which is the Atara program, as well as 3271, in both cases, we intend to go beyond the intraperitoneal administration route that has been used in advanced mesothelioma so far and to study the systemic route there. So in both cases, we will start in advanced mesothelioma, for example with 2271, with an IP route followed by an IV route.

And then, of course, for 3271, we believe that this particular construct, due to the benefit of not only the 1XX costimulatory domain and the PD-1 DNR, but also the EBV T cells and their natural biology in terms of trafficking and persisting, we believe that the systemic route is going to be a very exciting go-to study with that particular compound.

And our next question comes from Anup Rama with JPMorgan.

This is Tess on the call tonight for Anupam. Just one from us on the MS side of things. You are planning meeting with regulators by the end of this year for ATA188. I guess can you maybe describe for us what are the range of regulatory scenarios that we should be considering with those discussions?

Thank you. AJ, do you want to take that one?

Sure. Thank you for the question. A couple of key things that we're waiting for feedback from them on. Partly, we've already talked about the change in the endpoints. We'll get feedback on the change of endpoints. We'll get feedback on the time points that we're considering. We've talked in the past about 12 months versus 15 months time points based on some of the data that we're seeing in the Phase Ia as well as the open-label extension of the study.

And then I'm assuming you're also been talking about the scenarios on what are the next steps with this program. And it's hard to speculate on those things. We are discussing with them really all the different potential expedited pathways because we do feel like the program could qualify for really several of them. And those are things like fast track, breakthrough and RMAT. So we expect to receive feedback, specific feedback on every one of those pathways from the FDA.

Does it answer your question?

Great -- yes. That's great.

And our next question comes from the line of Maury Raycroft with Jefferies.

Congrats on the progress. And so the first one is on the ALLELE program. Just wondering if you could say how many sites are open currently and how many additional sites you still plan on opening over time.

Thank you, Maury. AJ, do you want to answer that question?

Sorry. Just to be -- just to make sure I have the question correctly, you were asking about how many more sites we're looking to open? I didn't catch that correctly.

How many we have open.

That's correct. How many are open and then how many more you plan on opening.

Got it. I believe we have something around in the mid-40s of sites opened. And the main areas that we're going to be continuing to have the site activity, site activation activity will probably be in Europe at this point. Because as you know, we've mentioned to you before that we've opened up Europe. We're seeing demand there from an expanded access perspective. So as Pascal alluded to, we want to make sure we're able to kind of meet the needs of the patients there. And it's always best to do that through a study environment than an expanded access environment. So that's where you'll probably see the majority of any other increases. But we've got plenty of sites open, up and running. And we just want to keep that access pathway open for patients as much as possible.

But just to be clear, we don't need to increase significantly the number of new sites. We're just having the sites that are open today and some that are in the process of being opened. And as AJ has said, Europe is very important in many aspects in terms of addressing specific patient needs and also gaining experience with tab-cel in Europe there. And we had recently not only the first compassionate use that we had, had for some time in Europe, but recently also the first patient enrolled in the ALLELE study in Europe. So that's great to create that base of experience with European centers with tab-cel in anticipation of future submission and launch in Europe.

Got it. That's helpful. And then for the PTLD study, if you can talk about time to response in the Phase III versus the Phase II, the EAP studies? And how often did you re-dose and switch haplotypes? And what have you learned based on that?

Yes. Jakob, do you want to take that one?

Yes, absolutely. And AJ can also contribute some information potentially. So as we mentioned in the beginning, these PTLD patients who've had prior therapy, either after HCT or SOT, have a very short survival, on the order of 2 to 3 months. So in the context of that, you really need a rapid response. So if you look at the academic data, Memorial Sloan Kettering in Phase II and so forth, we really do see a response that occurs on the order of weeks. And that's really important because these patients have a very, very short survival. So I can't comment on that aspect for the ALLELE study. We're only disclosing today the 50% response rate by IORA and the safety profile. But I can articulate those aspects of the historical data. Anything further to contribute, AJ?

No. I think just to underscore Jakob's point, although we're not going to give specifics on that, at the end of the day, this is a rapidly progressing disease. So you can intuit that in order for therapy to be successful, you're going to have to have a relatively rapid response.

And in terms of which number of switch therapies, any particular comment, AJ?

Yes. I think at this point, we're probably not going to be very specific on any switch at this time. I think just overall, probably a good overall statement for you is we're really not seeing anything that looks different from what we've seen in the prior MSK experience from those 2 perspectives.

Got it. That's very helpful. Maybe last quick question. For 188, have you had a chance to look at the 15-month data for the additional 2 patients in cohort 3 to inform the final dose in the randomized controlled study?

I mean let's wait for the Charcot presentation in a week's time.

And our next question comes from the line of Salveen Richter with Goldman Sachs.

Could you help us understand what has driven the variability with your data for tab-cel, where ORRs have ranged from 50% to 80%? And then secondly, have your projections on the commercial opportunity for tab-cel in EBV-positive patients changed here as you conducted these clinical trials? And if you could just remind us on what they are?

Maybe to address the first question, Jakob, and Kristin might address the second one.

Yes. So Salveen, thank you for the question. When I look at the data, especially having seen the interim analysis on ALLELE, a thing that actually impresses me is, if anything, the consistency of the data. So I do think, again, the safety profile is very consistent with what we've seen with the previous studies. And as Pascal mentioned, we've now treated near 300 patients with this therapy between the collaborators in our study. So I think there's deep consistency there. I also think we see consistency in terms of the rapidity of the response and the magnitude of response.

Now I think your point is well taken about 50% to 80% response rate. I still would categorize this as very robust response rate. And I think that's reflected also in the 2-year survival when you look at the historical experience. Now with the ALLELE study, that's obviously a registration-intense study, where we have really tightened up the eligibility criteria in order to produce an experiment that's going to be convincing to regulatory authorities to give us approval.

So I think when you think about the number of prior lines of therapy, the biomarker positivity, the performance status of the patients and all of those things, those are really tightly controlled within a study like ALLELE. And so the fact that we're getting a response rate here and the other characteristics of the performance of the therapy, which is very similar to the historical experience, gives us a great confidence.

Now I will say and remind that the 50% to 80% response rate in the historical experience are investigator reads. And what we're reporting today is the independent radiographic and oncologic response rate. So there is a little bit of a different way to read this, but obviously, the data in the ALLELE study is a more robust experiment not only from a patient enrollment standpoint but also from an efficacy standpoint where this is independently assessed. And frequently, what you see with independent assessment is response rates go down, if anything. But I will say here that the 50% response rate on the interim is a very robust data point.

Kristin, do you want to answer the question about how do we see the commercial potential there?

Yes. Thank you, Pascal, and thanks for the question, Salveen. So we're right where we thought we would be and where we want to be in terms of the commercial assessment. So you just heard Jakob kind of reiterate our interpretation of the data. And I would just add that, that profile is entirely consistent with how we've been thinking about what would represent a commercial opportunity for tab-cel.

So we continue to believe that there are several hundred patients in the U.S. who will benefit from this therapy. And the value proposition for tab-cel is, we believe, very strong between the response rates, the historical survival data that we've seen. Of course, that's historical, but we'll be watching very carefully to see how that evolves with ALLELE. And I also would like to emphasize that this is a very convenient therapy to deliver and for patients to take. We've heard about the safety profile and how that's being established, our ability and expectation to cover the needs of over 95% of patients at the time of launch, and pre-treatments are not required. And it's a very simple therapy with an IV infusion 5 to 10 minutes, 2 hours monitoring. And in the course of our study, we've seen patients treated in a variety of care settings as well. So we continue to be very confident in the commercial opportunity for tab-cel.

Does it address your question, Salveen?

Yes.

And our next question comes from the line of Tony Butler with ROTH Capital.

Just a very brief question around statements made on ALLELE about robust endpoints of 50%. I'm very respectful for that. If you look at the expansion cohorts in 205, and I'm just curious if you could say the same for 33% to 37%. I recognize that's a tremendous benefit over standard of care, but would you claim that to be robust as well? And second, on 188, with 16 patients in the open-label extension, are patients continue to be enrolled today in that open-label extension? Would you expect more patients to continue to enroll? I mean I might have thought so. You have 13 sites out. I would just think that there would be a good number of patients who would want to be enrolled in that expansion cohort.

Thank you, Tony, for your question. Jakob, do you want to address the first question about the way we see this particular data that we present at ESMO? And then AJ will take the question on ATA188.

Yes, absolutely. So Tony, thanks for the question. First and foremost, these patients with PID-LPD and AID-LPD, they really have a substantial unmet medical need. So again, these are patients who have failed available therapies, and there really are no approved therapies for these patients at all. And so I think the other point is that when you have a patient who's got an acquired immunodeficiency or an inborn immunodeficiency, giving these patients cytotoxic chemotherapy can actually be quite dangerous in terms of putting them at risk for getting infection and so forth.

So I think that with the very high unmet need, with the absolute lack of approved available therapies for these patients and then looking at this type of a chemo-free option for these patients that's not going to suppress their immune system further and then achieving response rates on the order of 33% to 37.5%, we think, is actually a meaningful result for these patients. And so I think this is a clinical benefit for these patients absolutely.

And AJ, do you want to answer about the number of patients we expect in OLE and why?

Sure. So just to add a bit of clarity, the open-label study is actually an open-label extension. So really the only people that we're enrolling in that study are people from the 4 cohorts that we've described previously. So clearly, you're looking at 24 maximum potential patients that would go in, to that study. And for that purpose, really, apart from 1 patient who moved out of the country and a couple of patients in the earliest cohorts where we had not actually decided on the right dose to move forward with the open-label extension, so then they moved on to other therapies, really everyone else has declared their interest in moving forward into the open-label extension. Any new patients that are interested in the study, we really want to actually move them into that randomized controlled trial, as you might imagine.

And maybe one other comment to make is, as we've reported, in the OLE, at ACTRIMS-ECTRIMS, we presented a handful of patients there. But as Pascal and I have articulated, there's going to be more OLE data that's going to be presented over the next 12 months or so. So you'll see data for more patients going forward as well.

And our next question comes from Michael DiFiore with Evercore ISI.

I just wanted to follow-up and dig in a little bit more on ATA188 for MS. It's already been answered. It sounds like the incremental data on cohort 4 patients Y and Z and how they did at 15 months could be presented next week. But I just wanted to -- I'm curious why you didn't even top line it today? Because it sounds like you're still undecided then whether to add the cohort 4 dose to the randomized controlled portion of the trial. That's one question.

And as a follow-up to that, if you could just remind us on the status of your discussions with the FDA in terms of exploring possible accelerated approval possibilities and whether they've occurred yet. And if cohort 4 patients Y and Z did not show sustained disability improvement at 15 months, I'm very curious to see how it may impact future discussions with regards to accelerated approval pathways.

Thank you, Mike. And I'll start answering the beginning of your question, and AJ will give you more details on the regulatory discussions there. I mean we have the data. We have made the decision regarding the dose. We're just going to announce that next week because we are protecting the embargo from short calling the data. So just to be clear. So you just have a week to wait, obviously just a bit of wait. AJ, any comment on the regulatory interactions?

Yes. Just from the timing perspective, we've actually had communication with FDA, we've submitted in fairly significant detail the protocol and a variety of questions that we have really around all of those expedited pathways that we talked about. We do expect response from them by the end of this year on that. So we would presume that we would probably communicate that to you all early next year.

Thank you. And ladies and gentlemen, I'm not showing any further questions at this time. It is now my pleasure to close the call. Thank you for participating. You may now disconnect.