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Edited Transcript of ATRA earnings conference call or presentation 9-May-19 12:30pm GMT

Q1 2019 Atara Biotherapeutics Inc Earnings Call

SOUTH SAN FRANCISCO May 24, 2019 (Thomson StreetEvents) -- Edited Transcript of Atara Biotherapeutics Inc earnings conference call or presentation Thursday, May 9, 2019 at 12:30:00pm GMT

TEXT version of Transcript

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Corporate Participants

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* Christopher M. Haqq

Atara Biotherapeutics, Inc. - Executive VP of R&D & Chief Scientific Officer

* Dietmar P. Berger

Atara Biotherapeutics, Inc. - Global Head of Research & Development

* Isaac E. Ciechanover

Atara Biotherapeutics, Inc. - President, CEO & Director

* John Craighead

Atara Biotherapeutics, Inc. - VP of IR & Corporate Communications

* Utpal Koppikar

Atara Biotherapeutics, Inc. - CFO

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Conference Call Participants

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* Anupam Rama

JP Morgan Chase & Co, Research Division - VP and Analyst

* John Lawrence Newman

Canaccord Genuity Limited, Research Division - Principal & Senior Healthcare Analyst

* Marc Alan Frahm

Cowen and Company, LLC, Research Division - VP

* Maryana Ilya Breitman

Goldman Sachs Group Inc., Research Division - Research Analyst

* Matthew Christopher Phipps

William Blair & Company L.L.C., Research Division - Analyst

* Maurice Thomas Raycroft

Jefferies LLC, Research Division - Equity Analyst

* Salim Qader Syed

Mizuho Securities USA LLC, Research Division - MD, Senior Biotechnology Analyst of Equity Research & Head of Biotechnology Research

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Presentation

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Operator [1]

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Good morning, ladies and gentlemen. Thank you for standing by, and welcome to the Atara Biotherapeutics First Quarter 2019 Financial Results and Corporate Update Conference Call. (Operator Instructions) As a reminder, this conference call will be recorded.

I will now turn the call over to Dr. John Craighead, Vice President of Investor Relations and Corporate Communications of Atara Biotherapeutics. Please go ahead, sir.

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John Craighead, Atara Biotherapeutics, Inc. - VP of IR & Corporate Communications [2]

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Thank you, operator. Good morning, everyone, and welcome to the Atara First Quarter 2019 Financial Results and Corporate Update Conference Call. Earlier this morning, we issued a press release providing an overview of the company's first quarter 2019 financial results and recent operational progress. Please note that this press release is available in the Investors & Media section at atarabio.com.

I'm joined on the call today by Dr. Isaac Ciechanover, President and Chief Executive Officer; Dr. Dietmar Berger, Global Head of R&D; and Utpal Koppikar, Chief Financial Officer. We'll begin with prepared comments from Isaac and Dietmar and then open the call for your questions.

We would like to remind listeners that 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 Atara's Chief Executive Officer and President, Dr. Isaac Ciechanover. Isaac?

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Isaac E. Ciechanover, Atara Biotherapeutics, Inc. - President, CEO & Director [3]

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Thank you, John, and thank you, everyone, for joining us this morning. We continue to make important progress advancing our T-cell immunotherapy programs across 3 major value drivers: tab-cel, multiple sclerosis and our next-generation CAR T program.

On today's call, we will provide an update on our recent progress and upcoming milestones. In a moment, Dr. Dietmar Berger, our Global Head of R&D, will discuss our clinical development programs in more detail, but I would like first to provide an update on our status of our ongoing tab-cel Phase III studies for patients with EBV+ PTLD.

Enrollment in these studies is proceeding slower than anticipated. The factors that make this condition challenging to identify and enroll patients in clinical studies are similar to other ultrarare and rapidly progressive diseases. We are aggressively implementing strategies to address these challenges that Dietmar will outline shortly and remain confident in our ability to successfully execute on our clinical development plan.

As we have mentioned previously, we are also in discussions with the FDA and EMA to align on a global regulatory strategy for tab-cel. The objective is to align on a tab-cel development plan for patients with EBV+ PTLD, which may all -- which may allow us to potentially expedite our U.S. regulatory submission. We are encouraged so far with our progress, and we expect the outcomes of these ongoing regulatory discussions in the first half of 2019.

Overall, we view our tab-cel pivotal development and regulatory progress to date as acknowledgment of the critical need to find new options to treat patients with this ultrarare and often life-threatening disease.

In parallel, we are continuing to advance our additional programs including ATA188 and ATA190 for multiple sclerosis. We remain on track to present initial Phase I safety results for our off-the-shelf, allogeneic ATA188 program at the Congress of the European Academy of Neurology, or EAN, in June of this year with additional efficacy and safety results expected later this year.

In addition, for our next-generation CAR T portfolio, our collaboration of MSK reported positive Phase I clinical results for their mesothelin-targeted CAR T immunotherapy for patients with solid tumors at the 2019 AACR Annual Meeting. Efficacy and safety results presented for patients with malignant pleural mesothelioma will also proceed with a PD-1 checkpoint inhibitor and lymphodepleting chemotherapy exceeded our expectations.

Following administration of a novel mesothelin-targeted CAR T, MSK investigators observed a 72% response rate in the subset of these patients. These data are among the first proof-of-concept results for CAR T to treat solid tumors. And given the strong fit with our next-generation platform, we will prioritize the development of mesothelin. We expect this to be our first CAR T program to enter the clinic with an IND anticipated in 2020.

We are also excited for our updated results from the MSK investigator-sponsored mesothelin-targeted CAR T study to be presented at ASCO in June.

I would now like to turn the call over to Dietmar who will provide a more detailed update on our clinical development programs. Dietmar?

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [4]

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Thank you, Isaac, and good morning, everyone. As Isaac mentioned earlier, I would like to provide some additional detail on the status of our ongoing tab-cel Phase III studies for patients with EBV+ PTLD. The factors that make this condition challenging to identify and develop patients in clinical studies are similar to other ultrarare and rapidly progressive diseases. For example, the window for patient recruitment during the course of disease progression is short and the overall incidence of the disease requires a substantial number of study sites.

As we advance our tab-cel program, we continue to gain multi-institution clinical experience and new insights about the epidemiology, diagnosis, treatment and prevention of EBV+ PTLD. These insights were not available when we initiated our studies. As an example, there is wide variation of PTLD incident rates depending on many factors in the transplant setting including the transplant type, level of immunosuppression, patient age and local standard of care at the transplant center.

We have gained experience regarding these components during the conduct of our clinical studies based on our work with leading physicians in the area and from interaction with EBV+PTLD patients and their families.

At the same time, our experience confirms that the median overall survival in EBV+PTLD patients following a solid organ or allogeneic hematopoietic cell transplant [will fail for] rituximab therapy is short, and PTLD is a life-threatening condition with a high unmet medical need.

Median survival in the hematopoietic stem cell transplant, patient population is approximately 50 to 56 days. In the solid organ transplant setting, 1-year survivor in patients with high-risk rituximab refractory EBV-PTLD is 36% with no patient expected to live beyond 2 years.

We are aggressively addressing enrollment by continuing to open additional sites now with a number of 32 and leveraging our significant thought leader network to identify potential EBV+ PTLD patients as early as possible. We have further optimized our patient recruitment strategies over the last year including earlier patient detection, outreach by our social media and patient advocacy, setting up referral centers and close collaboration with key transplant centers in both the HCT and SOT settings. In addition, we continue to see strong investigator physician and patient interests and are frequently providing tab-cel to patients in need under our early-access and single-patient use programs.

We now plan to submit the tab-cel European Conditional Marketing Authorization application based on the initial Phase III results in 2020. This is based partially on our current enrollment trends, which now precludes the submission by the last possible European filing window this year. But more importantly, we believe this updated European filing strategy provides us flexibility to align on a tab-cel development, plan for patients with EBV-PTLD with both FDA and EMA and to finalize time lines for our U.S. regulatory submission. Again, we are encouraged with our progress, and we expect the outcomes of these ongoing regulatory discussions in the first half of 2019.

To ensure the integrity of the ongoing open-label tab-cel Phase III studies, the company anticipates disclosing initial top line EBV-PTLD results following acceptance of the EMA regulatory submission.

Moving now to our multiple sclerosis and next-generation CAR T pipeline programs. We have made consistent progress on both as noted in our press release this morning. Our programs in MS are on track. We are advancing an off-the-shelf allogeneic ATA188 Phase I study in patients with progressive MS with initial safety results expected to be presented at EIN this June. We also plan to present additional safety data and initial efficacy results from that study at the scientific Congress in the second half of 2019. In addition, we expect to initiate a randomized study of autologous ATA190 in progressive MS patients in the second half of this year.

Turning to next-generation CAR T immunotherapy programs. We are excited about our recent progress. Our collaborators at Memorial Sloan Kettering Cancer Center recently presented positive Phase I results for the mesothelin-targeted CAR T immunotherapy in patients with pleural solid tumors at AACR in March. As Isaac mentioned, we were encouraged by the 72% response rate in the subset of patients, and we look forward to MSK's presentation of updated results at ASCO in June.

Based on the MSK data, we are prioritizing our development of a next-generation mesothelin-targeted CAR T immunotherapy with an MSK novel 1XX CAR signaling domain and the PD-1 dominant negative receptor for patients with mesothelin-associated solid tumors with an IND for this program planned in 2020. Using more physiologic T-cell activation and targeted checkpoint inhibition offers the potential for a next-generation CAR T-cell approach in different solid tumor settings.

Atara is expecting presentations highlighting tab-cel and our next-generation CAR T immunotherapy technology at ASCO 2019.

I would now like to turn the call back

(technical difficulty)

can go ahead and take your questions. Operator?

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Questions and Answers

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Operator [1]

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(Operator Instructions) We have a question from the line of Anupam Rama of JPMorgan.

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Anupam Rama, JP Morgan Chase & Co, Research Division - VP and Analyst [2]

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On PTLD enrollment dynamic, I think the press release said you have 32 sites open and you're planning on opening more. What are the time lines for this [and is there a] regional focus here for site initiation?

And then just another quick question on the Tuesday oral presentation for mesothelin CAR T, this data sounds like they're going to be updated from AACR. So perhaps you can help us understand the scope of the new data we'll be getting.

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [3]

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Yes. Thank you, Anupam, for the question. With regards to PTLD and the enrollment dynamics, we are gaining process opening new sites, and we're also planning to extend the geography. Where the study is currently focused primarily on the U.S., we're planning to expand to other regions consecutively and aggressively. Looking at this, I'd point out that this is not the only activity [realistically, and we're looking at a slew of recruitment strategies that we have started over the last year. Those [look] at earlier patient detection, outreach via social media, patient advocacy. We set up referral centers because sometimes these patients have to be transferred from one site to the other, and we collaborate very closely with key transplant centers in both the HCT and SOT settings. So we are confident that we will be able to execute on these studies.

Regarding the mesothelin presentation at AACR, you are correct. This will be an update of the current data that you have seen at AACR. So we are expecting more details on the patient population, potentially more patients and product details on the efficacy and safety. But at this point in time, we cannot say more about that.

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Operator [4]

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Another question from the line of John Newman of Canaccord.

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John Lawrence Newman, Canaccord Genuity Limited, Research Division - Principal & Senior Healthcare Analyst [5]

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So I'm just curious. I know you don't -- you probably don't want to divulge details. But with regard to the work that you're currently doing with the expanded access program, will you be able to incorporate those data into any regulatory filing with either the FDA or Europe? In -- on Anupam's question on the mesothelin CAR T.

It does sound like there will be data from some additional patients. Just wondered if you can give us a sense of the sort of potentially how many.

And then also on your IND filing for CAR T in 2020, should we assume that that's initially an autologous product?

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [6]

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So thanks, John. With regards to the first question regarding the early-access program, our concept is to present the totality of data to regulatory authorities, and the totality of data includes a broader set of experience including our pivotal trials, but then also the Memorial Sloan Kettering studies that have happened over several years, obviously. And this also includes the early-access program. From the early-access program, and this is really an early-access study also, from the early-access program, you will also obtain safety and efficacy information. And we have published some of that information on various tumor types -- actually, at different [meetings] the most recent publication being on leiomyosarcoma last year.

With regards to the mesothelioma data, you're correct. We are expecting more patients. I cannot provide details at this point because the ASCO presentation is under embargo. But obviously, these are data from the ongoing study, and the study has continued recruitment as -- with the same case study as before.

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Isaac E. Ciechanover, Atara Biotherapeutics, Inc. - President, CEO & Director [7]

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This is Isaac. John, just one addition to the EAP to give you some color. Because these are life-threatening diseases, patients who, for example, can't make it to the study site, we ensure at Atara that every patient who wants access to this therapy gets it. And so there are patients, for example, who do fall out. The timing is relatively short for some of these patients who are progressing in their disease. And so that data is important and will be part of our totality of the information that both agencies look at.

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [8]

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And your final question regarding mesothelin, yes, initially this is an autologous program with the objective to later on put this onto our allogeneic platform.

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Isaac E. Ciechanover, Atara Biotherapeutics, Inc. - President, CEO & Director [9]

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So it's very similar to what we did with the 188 program where we get our proof-of-concept for this next-generation module with 1XX and PD-1 knockout, then we can then move very rapidly into making allo versions of it, very similar to how we did 188 -- 190 program then move forward to 188.

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Operator [10]

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We have another question from the line of Salim Syed of Mizuho.

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Salim Qader Syed, Mizuho Securities USA LLC, Research Division - MD, Senior Biotechnology Analyst of Equity Research & Head of Biotechnology Research [11]

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Just a couple for me. One on MS. Given that, I guess, this now becomes the more important catalyst for the year given the delay in the PTLD, how should we be thinking about success of the Phase I study here? I know you guys described this in the past as being a high-risk, high-reward program. So any color on how investors should interpret the data when we get it? What do you define as a successful outcome here?

And then the second question, just on the commercial opportunity of PTLD. Given the delay in enrollment in the clinical trial, is there any read across how you guys are thinking about the commercial opportunity in PTLD?

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [12]

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All right. Thank you, Salim. Regarding the MS study, once again, the MS program is on track. We are presenting the safety data at year-end and the efficacy data -- the initial efficacy data and additional safety data during the year. The -- this is a safety study. This is a Phase I dose-escalation study of the allogeneic program. We are excited about this because this is the first time that we had an allogeneic T-cell immunotherapy in -- basically in neuro inflammatory disease, right? And a positive study at the initial data set will be, yes, it's safe. We can provide this to patients with a dose-escalation setting. And then obviously we're very interested in other endpoints and other outcomes. We're planning to present those at the -- later during the year, and we're looking at different types of endpoints including the EDSS score, including brain imaging, including biomarkers, but these will be later during the year.

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Christopher M. Haqq, Atara Biotherapeutics, Inc. - Executive VP of R&D & Chief Scientific Officer [13]

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And Salim, in regards to just the read through from the trial to the market. We think PTLD is a very important market for us and for our patients. We have a therapy that has curative intent, is cost-effective and has a strong value proposition and a great read-through by both physicians and patients. In addition, PTLD, as we said, is an ultrarare disease, and the number of patients that qualify for our studies is smaller. And as such, using the Phase III as a surrogate for ultimate market, I don't think it's -- this is not how we look at it. What we see is in regards to the demand both from our Phase III studies as well as the EAP, and as Dietmar mentioned, SPUs for patients where we'll have to send the therapy to their site that isn't associated with the trial. All that gives us a lot of comfort as well as the MSK experience of the previous data that you see in regards to the disease state and just the unfortunate outcome of that is to -- occur in these patients that don't get this therapy.

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Utpal Koppikar, Atara Biotherapeutics, Inc. - CFO [14]

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Salim, it's Utpal. I just want to add to what Isaac said. Dietmar alluded to this earlier on the call where we've seen a wide variation of EBV+ PTLD incident rates. And there are several factors, right? So this experience in standard of care of at the transplant center, the type of transplant [ATT] versus SOT. There's variation in the organ type, the level of and the degree of immunosuppression and pediatric versus adult patients. The age matters as well. So what we do want to net out for you is that rates of HCT, SOT incident that we've seen is in the low single-digit range. It's blended across all these factors. And beyond PTLD, what we've seen from EAP and the EBV positive malignancies in the patients is [past cells] more than just PTLD. It's representing along with NPC a pipeline or product opportunity.

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Operator [15]

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Another question from the line of Matt Phipps of William Blair.

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Matthew Christopher Phipps, William Blair & Company L.L.C., Research Division - Analyst [16]

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So if I can start, I mean, the -- you still say the regulatory discussions are on track for kind of concluding in the first half, yet you're pushing out the EMA filing by a year. So that would lead one to assume that the FDA maybe is not as interested in going for this faster approval and wants more of a complete dataset. I guess my question is can you define what you mean by initial Phase III results, the term you guys used in conjunction with the EMA filing? But is that initial response rate from all 35 patients?

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [17]

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Thank you, Matt. Let me take your questions one at a time. So we're currently in discussions with regulatory authorities, and I would call this regulatory strategy discussion. This is about the overall submission package, the totality of data. These discussions are progressing well. We had announced that we think there will be some by the end of the first half of the year, and we're still in that phase. We cannot update exactly on those discussions at this point in time because they're ongoing, but we are encouraged by the progress of those discussions.

Then regarding the time line of the European submission, I want to point out that we have provided a wide range here purposefully, and it's based partially on the current enrollment trend. We have specific windows where you submit in Europe specific accepting states they have. The latest EU filing window this year is in November, and we realized very recently that the enrollment trend now precludes the submission by that latest EU filing window.

But more importantly, right, this wide range is based on the ongoing discussions with the regulatory authorities in both the U.S. and Europe, right? The objective of these discussions again is to align on a global tab-cel development plan and align on a global development plan that's really based on totality of data including all the different data sources that we have similar to the current plan that already exists for the conditional marketing authorization submission in Europe.

As a potential result of these discussions, we hope to finalize the timing of our U.S. regulatory submission and really to give you more of an update then by the end of the first half of the year. However, as these discussions are still ongoing, we provided this wide submission time frame in order to anticipate a range of possible regulatory discussion outcomes.

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Isaac E. Ciechanover, Atara Biotherapeutics, Inc. - President, CEO & Director [18]

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The only thing I would add, Matt, is, as Dietmar said, we provided this wide range in order to give us flexibility in regards to where the FDA discussions will net out. So I wouldn't make a conclusion in your question that this is already alluding to FDA commentary where they're not supportive. In fact, they've been very supportive with us, and that's why we feel comfortable that we'll be able to tell you in '19. It's just that at this point, we are in those discussions and we can't make commentary around it.

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [19]

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Yes. And actually, on the FDA breakthrough, right, and on the EMA prime, you're actually encouraged to have these ongoing discussions with both agencies and it is supported throughout the progress, and they're really open to have those -- to having those discussions.

Regarding the subsets, right, regarding the number of patients, our initial Phase III results, the regulatory strategy is really based on this concept of totality of data, which means that you look at the overall experience you have, and that allows you to submit based on a subset of data for the pivotal study. As these regulatory discussions are ongoing, we can't speak about exactly what that subset is, but the initial results that we will see are exactly that subset of preplanned analysis.

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Matthew Christopher Phipps, William Blair & Company L.L.C., Research Division - Analyst [20]

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Got it. Okay. And then regarding the mesothelin CAR, I mean obviously the data that you shared was very encouraging. When you guys move forward next year with your own next-gen version, do you think you'll initially start with the local regional delivery for mesothelioma and the pleural cavity? Or would you go kind of right to IV and try to include some other mesothelin-positive tumors? I know they're also, I believe, starting to look at triple-negative breast cancer at MSK as well.

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [21]

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We have not finalized our clinical strategy obviously, and this is still under discussion. I want to say the data from MSK are intriguing, and they are based on a local regional administration into the intrapleural space. So this is definitely an area that we will study. Besides that, we will obviously study the IV application as well.

The preclinical data for the 1XX activating domain are really encouraging. Also, the preclinical data have been seen for the PD1 domain negative receptor. That's where we're thinking that with a next-generation product beyond the intrapleural application of the local region application, how can this product be applied also intravenously to other types of tumors? And you're right, breast cancer is one tumor through [active] breast cancer, high unmet medical need, but also a subset of those tumors is mesothelin-positive, but there's a variety of other tumors there that we're thinking of rising. And if you look at the types of mesothelin-positive tumors, then you go look to pancreatic cancer, ovarian cancer and other types of diseases. So we don't have to think carefully about the development plan overall.

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Isaac E. Ciechanover, Atara Biotherapeutics, Inc. - President, CEO & Director [22]

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Yes. And the only other thing I would add, Matt, is as you can imagine, even in our own commentary, this current program exceeded expectations. So the bulk of the data is in mesothelioma patients and that you should assume that this is going to be the center of where we take this therapy. It's -- efficacy data is, as we say, intriguing. The safety data is the other important part that really differentiates this molecule. And demand and interest in this program has only increased with the publication in AACR, which is why we're going to have an update in June at ASCO. So I really -- I would say that we're absolutely interested in broader indication and other administration site, but intrapleural and mesothelioma as the primary should still be the core where initially this program will be developed.

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Operator [23]

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We have another question from the line of Salveen Richter of Goldman Sachs.

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Maryana Ilya Breitman, Goldman Sachs Group Inc., Research Division - Research Analyst [24]

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It's Maryana Breitman for Salveen. I have a couple. One of them is you have mentioned a wide variation in incident rates of PTLD, and I was wondering if we could get a little more clarity especially as regards to [lympho] depletion product calls, also how that sort of -- has different -- how that involves these incident rates in the U.S. versus Europe and in the U.S., the sort of like MSK product calls versus West Coast product calls. Like how should we be thinking about that?

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [25]

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Yes. Thank you for the question. This goes into a lot of detail of the biology of PTLD. And eventually, what we're speaking about here is immunosuppression associated with lymphoproliferative disease. There's also a recent paper coming out of Stanford that describes these really in that way, and they're obviously -- the level of immunosuppression becomes really important, and this is where the T-cell [exceed in] programs around the transplant. And any type of immunosuppressive activities actually become important.

I'm answering the question that way because not only does the T-cell depletion, also the other types of sectors that come together at the transplant center. Eventually, we're talking about the mix between prevention of PTLD, but then also treatment afterwards. We do see the treatment paradigm is actually quite stable. But on the prevention side, some of those factors that you're talking about, for example, less intensive T-cell decision regiments or the use of post-transplant cyclophosphamides as well as more aggressive monitoring and treatment of EBV positive [female] with rituximab all play a role.

The answer has to be broader because these factors are really different at the individual sites, and in some sites you see an increase in the immunosuppressive regimens. In other sites, you see a decrease. And that directly impacts the incidence of PTLD at that site, and we're learning as we go along and as we work with those sites about the exact effect at each specific site.

When we talk about Europe versus the U.S., overall, the standard of care in the transplant setting is global with a lot of site-specific variation. It's not even variation between Europe and the U.S., it's really site-specific variation. And you find sites in Europe that in fact do their transplant as they do with [their options]. And you find other sites that orient themselves more towards other U.S. sites. And that variation needs to be taken into account. But overall, what we provided as like a median in the -- basically saying it's a low single-digit -- low to medium single-digit range in incidents across all the sites and across all these factors. That's I think one of our key conclusions.

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Maryana Ilya Breitman, Goldman Sachs Group Inc., Research Division - Research Analyst [26]

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Got it. I had another question on the next-generation CAR T. There were prior trials where mesothelin CAR T were used at National Cancer Institute, and I believe the response rate was fairly low. I think they were not done in the presence of immunosuppressive checkpoint inhibitors. I am -- I'm wondering how do you explain the difference in response rates that MSK has gotten versus NCI.

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [27]

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Thank you for the question. They were obviously different studies that were looking at mesothelin-targeted therapeutics. I think there are various factors here, right? One is this is a different product, right? This is a different mesothelin-targeting domain, a different scFv that has been very carefully selected. And I think that scFV and -- we have licensed that. scFv is one key component, and really we're talking about direct binding and the different binding and the characteristic that's basically the key of that specific scFv.

And the other factor here is, is it intrapleural administration? I think at this point in time, we don't know eventually what the intrapleural administration does versus the IV administration, but we'll definitely achieve high cell doses and the size of the tumor when you give the cells intrapleurally.

And then the addition of the checkpoint inhibitor may play a role. Obviously, the checkpoint inhibitor in itself, there are studies with check on the inhibitor alone that gives you a specific response rate. The studies that MSK has been demonstrating, obviously have much higher response rates than what has been seen in these earlier trials. So we're not talking about an effect of the checkpoint inhibitor alone. We're talking about an effect of a checkpoint inhibitor together with cells because you're really maintaining activity of the cells. You're adding to the [consistency]. You're unleashing the T-cell component eventually with a checkpoint inhibitor. So there are various factors that are different. Eventually, what really counts for me is the clinical efficacy of the observations that has been seen in those patients, and this is obviously very encouraging. And we will follow through on that.

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Isaac E. Ciechanover, Atara Biotherapeutics, Inc. - President, CEO & Director [28]

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The only thing I would add to that last comment is it's still a small subset of data, but we know what a baseline of the PD-1 inhibition does in this condition. And so the [additive affect] of the combination is clear. We've also had -- or MSK is having experienced single patients where response rates were even seen before the PD-1 was administered. And so the synergy of the two and also our addition of the PD-1 knockout in the next generation, I think, is what ultimately -- is a factor in really differentiating this product from prior programs. The other key [component] is you talk about response rate, but safety is also the key issue in all of this. Those earlier studies as well as other studies really were even able to achieve efficacy because of the product itself wasn't tolerated. And so from -- one of the things that we're really intrigued by this program is the ability to actually administer this and give multiple doses to patients over the long period of time. Because in these conditions, I think that's necessary in order to get a durable response.

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Operator [29]

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We have another question from the line of Marc Frahm of Cowen and Company.

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Marc Alan Frahm, Cowen and Company, LLC, Research Division - VP [30]

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Can you guys provide some metrics maybe on exactly where you are on enrollment? And then you mentioned opening more sites. So clinically, where would you like to be? Is the right number 40? Is it 50? What's the right number of sites over maybe the next 6 months?

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [31]

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So we cannot comment on the effect that is of enrollment and the patient population in ongoing open-label Phase III study. And we haven't done that before.

For the additional sites, we're now at a number of 32. We have really not spoken about the overall number of sites that we're looking at. And by the way, that number is changing, right? And we realize that enrollment is slow. Obviously, you add more sites. We're currently in the process of adding more sites, and we will also expand the geographic footprint beyond the U.S. And then we think that adding sites, for example, Europe, will be another key factor that allows us to recruit really more expeditiously.

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Isaac E. Ciechanover, Atara Biotherapeutics, Inc. - President, CEO & Director [32]

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Now we're also far along into this study. So as we mentioned, European submission had a cutoff date of November, simply because that's the last date that they're willing to accept a submission. And so with the additional sites, these are all planned for us. We are obviously increasing the numbers. But we're far along into the study that -- I think a lot of the other aspects besides first 4 site additions, like advocacy, outreach, trying to identify the patients when they first develop PTLD. So we really try to create a backlog earlier on because when -- ultimately, it's time to give a therapy, that window is relatively short. And so we've taken really a proactive approach to identify patients really early that may become eligible for this study or the EAP program. And that active surveillance is a really key part of what we're doing to ensure that the study is [in house], and we're able to complete them in a timely manner.

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Marc Alan Frahm, Cowen and Company, LLC, Research Division - VP [33]

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Okay. Great. And then turning to the MS program. Can you just remind us what kind of a dose-escalation scheme that you're using in 188 and kind of when we get these data updates first at EAM, but then also in the second half when we start to see efficacy data. How does this compare to what was seen before with 190?

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [34]

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We're currently in -- thanks for the question. We're currently in the dose-escalation phase. Obviously, details will be at that EAN abstract. But if you think about this just from a general perspective, we have published data together with Michael Pender, right, on the autologous 190 program. Those data were generated at a specific -- also initially dose-escalation, but then final dose of T cells per patient, right? We started our study, and that's what you will do with an allogeneic program. You start at a lower dose, and then you escalate basically to that dose and potentially even beyond. And you will see that data at EAN. What's really important with all of this, then obviously it's in the progressive dose cohorts, expansion is how the safety turned out. And that's what you will see at EAN, but we're covering a range of doses, and you will see data on the clinically relevant dose.

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Operator [35]

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We have another question from the line of Maury Raycroft of Jefferies.

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Maurice Thomas Raycroft, Jefferies LLC, Research Division - Equity Analyst [36]

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First one is just on tab-cel and the EBV+ PTLD trial. I'm just wondering if you can provide more color on whether it's the number of patients out there that's lower than expected or whether it's more weighted toward not getting to the patients soon enough to give them treatment.

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [37]

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Thanks for the question. It's always a mixture of both, right? Now eventually, PTLD is an ultrarare disease. And then we're talking about a pivotal trial here where you usually try to, and we are, to have a homogeneous patient population. So the number of patients for this trial is even smaller. What makes this especially challenging and what we've also learned is that it's the rapid progression, right? Once patients are identified for the trial, you need to be able to provide treatment very, very rapidly, which means you don't have the time to open an additional site for a patient that is coming out, right? You need to have the site open. Or you have to transfer the patient to another site, right?

The median survival of patients in the relapse refractory setting after HCT is 16 to 56 days, right? Physicians identify the patients. They come to us. We need to deliver really quickly. Eventually, that is also why an allogeneic product make so much sense for these patients because you don't have time to think about other treatment approaches. You have to be able to deliver product within 3 to 5 days as we want to and as we can do. With tab-cel, with the allogeneic products, so that value proposition is absolutely there. And the fact that we see all those requests for the early access program, the fact that we have an NPC study, the fact that we're planning for a basket trial, really that explores the overall, I want to say, value and market opportunity for tab-cel.

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Maurice Thomas Raycroft, Jefferies LLC, Research Division - Equity Analyst [38]

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Got it. That's very helpful. And then just as a follow-up to that, I'm wondering if you're noticing any differences between SOT and HCT that you can comment on?

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [39]

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No real differences in the study. Obviously, if you look at the epidemiology, there's more solid organ transplant cases, which means there's also more opportunity to have PTLD. Also in the solid organ transplant setting, it's very dependent on the organ type, and the PTLD occurs basically with a delay. Because you've got this years and years of immunosuppression. So you can see PTLD in very different settings in the solid organ transplant arena, right? As you can see it either at the transplant center or you can even see it at community sites where those patients are treated over the course of like the long-term follow-up of their transplant.

And that's another key learning for us, right? What are the sites that you need to go to? How do you approach, for example, these community centers? How do you include them? That's where we get to this concept of the referral centers, right, where we then can treat PTLD. So there's a lot of key learnings. And there are slight differences between HCT and SOT. Eventually, I want to point out that PTLD is PTLD is PTLD, right? The biology of the immunosuppression associated with [lymphatic] disease is the same in these different areas, and the response to tab-cel is also very similar in those different areas.

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Maurice Thomas Raycroft, Jefferies LLC, Research Division - Equity Analyst [40]

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Got it. And the last question is on the mesothelin program. Pretty interesting that you guys are administering intrapleurally or the therapy is being administered intrapleurally, and you're seeing such a nice efficacy. And I'm wondering if that route of administration, if there's understanding, if that's making a big difference with having the cells trapped in that area and if you could comment on that.

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [41]

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Eventually, the answer to this has to be we don't know, right, because nobody has ever studied the intrapleural versus IV so that you could really come to a comparison. But obviously, we have these very positive data with the intrapleural administration, with the additional checkpoint inhibition and with the specific product that they use with specific kind of a specific scFv. So we will follow up on this, and all this will go into how we design our development program for the second generation product.

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Maurice Thomas Raycroft, Jefferies LLC, Research Division - Equity Analyst [42]

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Got it. Do you have a sense of whether you're getting better-than-expected persistence based on intrapleural delivery, I guess?

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Dietmar P. Berger, Atara Biotherapeutics, Inc. - Global Head of Research & Development [43]

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Yes. Some of the facilities data were already at the AACR, right, and Prasad Adusumilli, the investigator, was demonstrating that he does see mesothelin-targeting CAR T cells in the circulation for an extended period of time. So he was, at that point in time, interpreting that as better than expected facilities. We'll potentially see updates with that at ASCO as well.

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Operator [44]

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This concludes our question-and-answer session. And I will now turn the call back over to Dr. Isaac Ciechanover for closing remarks.

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Isaac E. Ciechanover, Atara Biotherapeutics, Inc. - President, CEO & Director [45]

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Thank you. I want to thank everyone for taking the time to join us on the call today. I also wish to acknowledge the many extraordinary contributions by Atara employees that enabled us to reach this point. I have the utmost confidence in our team to achieve many important milestones ahead. And when you see those names, he or she will be in a great position to further realize Atara's mission to transform the lives of patients with serious diseases. Thank you all.

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Operator [46]

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This concludes today's conference call. You may now all disconnect.