U.S. Markets close in 32 mins

Edited Transcript of ADAP earnings conference call or presentation 1-Aug-19 12:00pm GMT

Q2 2019 Adaptimmune Therapeutics PLC Earnings Call

Abingdon, Oxforshire Aug 4, 2019 (Thomson StreetEvents) -- Edited Transcript of Adaptimmune Therapeutics PLC earnings conference call or presentation Thursday, August 1, 2019 at 12:00:00pm GMT

TEXT version of Transcript

================================================================================

Corporate Participants

================================================================================

* Adrian Rawcliffe

Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer

* James Julian Noble

Adaptimmune Therapeutics plc - CEO & Director

* Juli P. Miller

Adaptimmune Therapeutics plc - Director of IR

* Rafael Amado

Adaptimmune Therapeutics plc - President of Research & Development

================================================================================

Conference Call Participants

================================================================================

* Charles Anthony Butler

Roth Capital Partners, LLC, Research Division - MD, Senior Equity Analyst & Head of Biotechnology Research

* James William Birchenough

Wells Fargo Securities, LLC, Research Division - MD and Senior Biotechnology Analyst

* Keith Tapper

* Kelsey Beatrice Goodwin

Guggenheim Securities, LLC, Research Division - Associate

* Marc Alan Frahm

Cowen and Company, LLC, Research Division - VP

* Waleed Abdel-Naby

SunTrust Robinson Humphrey, Inc., Research Division - Research Analyst

* Wei Ji Chang

SVB Leerink LLC, Research Division - MD of Emerging Oncology & Senior Research Analyst

================================================================================

Presentation

--------------------------------------------------------------------------------

Operator [1]

--------------------------------------------------------------------------------

Good morning, and welcome to the second quarter of 2019 Adaptimmune earnings conference call. My name is Carla, and I will be your conference operator today. (Operator Instructions)

And now I would like to turn the call over to Juli Miller. Go ahead, please.

--------------------------------------------------------------------------------

Juli P. Miller, Adaptimmune Therapeutics plc - Director of IR [2]

--------------------------------------------------------------------------------

Good morning, and welcome to Adaptimmune's conference call to discuss our second quarter 2019 financial results and other business update. We issued 2 press releases earlier this morning, and I would ask you to please review the full text of our forward-looking statements there. As a brief reminder, we anticipate making projections during this call and actual results could differ materially due to a number of factors, including those outlined in our latest filings with the SEC.

James Noble, our Chief Executive Officer; Adrian Rawcliffe, incoming Adaptimmune's CEO; and Rafael Amado, our President of Research and Development are with me for the prepared portion of this call. Bill Bertrand, our Chief Operating Officer; Helen Tayton-Martin, our Chief Business Officer and Co-Founder; and John Lunger, our recently named Chief Patient Supply Officer will be available for Q&A after the prepared portion.

With that, I'll turn the call over to James Noble. James?

--------------------------------------------------------------------------------

James Julian Noble, Adaptimmune Therapeutics plc - CEO & Director [3]

--------------------------------------------------------------------------------

Thank you, Julie. And good morning, everyone, and thank you for joining us for what will be my last quarterly call for Adaptimmune as CEO. I've spent 20 years in the field of T-cell receptors, and I am convinced that they will have an important role in treating patients. We have already seen compelling data in sarcoma with ADP-A2M4 and have recently started a trial with the next-generation SPEAR T-cell and a combination trial with low-dose radiation to improve the depth and durability of responses.

It's my final pleasure as CEO to be handing over to Adrian. I know that he will do an excellent job in taking the company through its next evolution towards commercialization. The changes that he is already introducing and the plans for the future will bring energy and focus to the tasks ahead, accelerating execution across the company.

And with that, I will now turn it over to Adrian. Adrian?

--------------------------------------------------------------------------------

Adrian Rawcliffe, Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer [4]

--------------------------------------------------------------------------------

Thank you, James. And I want to personally thank you for your leadership of the company since the start and your support of me and the rest of the executive team during the transition.

After a month's transition, I want to share a little more about 3 areas that I'll be focusing on in the coming months. First, I want to continue increasing our focus on rapid execution. We've always had great science, and we've always had a high potential pipeline of SPEAR T-cells. However, we need to focus on rapid execution of this to bring benefit to patients with cancer and to our shareholders.

You may have noticed this increased pace already. Since the clinical update in May, we've started the SPEARHEAD-1 trial, the SURPASS trial and the low-dose radiation sub-study. The SPEARHEAD-1 trial in sarcoma is our first late-stage trial. The SURPASS trial is our first next-generation trial. And the low-dose radiation sub-study with ADP-A2M4 is the first trial we've initiated to improve T-cell traffic into tumors. These 3 trials started were only announced at our May update, and we'll have initial data readouts of the SURPASS trial and the radiation sub-study next year along with initial data in our ongoing AFP program. We also expect to have completed the futility analysis in our SPEARHEAD-1 trial by then.

Focusing on rapid execution also means being clear about what we won't do. And we've made the decision to wrap up both of the ADP-A2M10 trials, the triple tumor and the lung trial, by the end of 2019. Feeding into this decision was the overlapping indications that express MAGE-A4 and MAGE-A10 and the fact that MAGE-A4 expression seems higher than MAGE-A10 across all indications where we have tested MAGE-A10 expression. So it makes sense for us to focus on MAGE-A4.

Looking forward, you'll see changes designed to improve the pace of clinical recruitment, particularly in early-stage trials and to enhance our ability to convert translational insights into improved treatments.

Secondly, I want to build on the expertise of the company to be ready to launch our first product in 2022. This obviously starts with the rapid delivery of the SPEARHEAD-1 trial, including implementations of things such as the Vineti software announced today and building our readiness to deliver products at commercial scale.

You should view the promotion of John Lunger, the Chief Patient Supply Officer as a strong statement of our intent in this direction. John has been our SVP Manufacturing and Supply Chain and has been responsible with other members of the CMC leadership for the creation of Adaptimmune's integrated manufacturing and supply operations. He will now lead development of the capabilities and build the scale we need to deliver our products to patients for clinical and commercial stages.

Finally, I want to leverage the integrated capabilities we've built across research, development and manufacturing and supply and apply this world-class expertise across cell therapy more broadly. A near-term example includes driving our stem cell-derived allogeneic program, which is applicable to all T-cells, including both CAR-T and TCRs and which we believe is amongst the most advanced in this field. This includes progressing the development of the manufacturing process for these allogeneic T-cells. We provided an update at ASGCT this year. The program continues to move apace, and we look forward to giving you updates in due course. I will provide more details of our strategy and plans over the course of the coming months.

We also announced this morning that Rafael Amado, our President of R&D, will be leaving the company on August 12. We have a great debt to Rafael for his clinical expertise and everything that he and his team have done to get us to where we are today, embarking on late-stage development of our first SPEAR T-cell therapy with the aim of being on the market in 2022. And so for the first time for me, and actually, the last time, I'd like to turn the call over to Rafael for a clinical update. Rafael?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [5]

--------------------------------------------------------------------------------

Thank you, Ad, and thanks, everyone, for joining us. As Ad said, we have made great progress over the last month with the start of these 3 new trials. In addition, we continue to focus on our translational research and aim to learn from every patient. We're gaining a greater understanding of how to best enable our SPEAR T-cells to expand, infiltrate solid tumors and induce cytotoxicity. We're learning about factors that influence response to SPEAR T-cells, and we are implementing new approaches that we think may make our SPEAR T-cells more effective. We're also learning about target expression along with other markers in tumor tissue before and after treatment. We will continue to evaluate new technologies to improve our SPEAR T-cells based on our translational findings, and we will investigate further enhancements, such as allogenic sources, based on these data.

Likewise, we continue to learn about the safety of lymphodepletion regimens and of our products. Since our update in May, there have been 2 serious adverse event reports of severe prolonged pancytopenia. These events occurred in 1 patient with lung cancer who received 2 cycles of lymphodepletion and ADP-A2M10, and in 1 patient with Sarcoma who received a single cycle of lymphodepletion followed by ADP-A2M4. Both these patients subsequently died of complications of prolonged pancytopenia. One additional patient had Grade 3 neurotoxicity that was probably related to ADP-A2M4. The patient subsequently died of a stroke that we believe was unrelated to SPEAR T-cell therapy. All 3 of these patients had received a high lymphodepletion regimen, which consists of fludarabine 30 milligrams per meter square per day for 4 days and cyclophosphamide 1.8 grams per meter square per day for 2 days. We believe that the higher dose of cyclophosphamide, used as part of the preconditioning regimen in the first 2 patients, likely contributed to this SAEs. To mitigate the further risk of prolonged pancytopenia, the protocols for our trials have been amended to include changes in eligibility criteria and a reversion to the previously used lower dose of cyclophosphamide. We have been communicating frequently with the Food and Drug Administration, responding to queries, and the trials have continued with these changes.

We have made great progress throughout the past year, completing dose escalation across the ADP-A2M4 and ADP-A2M10 trials, initiating 3 new trials within the last month.

We're also making progress with our AFP trial, which is occurring at 1 billion cells without evidence of hepatotoxicity and with clearer evidence of cell trafficking into hepatocellular tumors. We plan to give more clinical updates at medical conferences as the data evolve.

Of note, the sarcoma data from our ADP-A2M4 trial will be updated at an oral presentation at ESMO later this fall.

On a personal note, I would like to thank all my colleagues here at Adaptimmune, especially those working in R&D. It has been a great experience working with you, and I look forward to seeing how Adaptimmune progresses the current and improved products over the coming months and years.

And now I will turn the call to Ad. Ad?

--------------------------------------------------------------------------------

Adrian Rawcliffe, Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer [6]

--------------------------------------------------------------------------------

Thanks, Rafael. We are at pivotal moment for Adaptimmune, and I am excited to lead the company forward with the aim of having a commercial product in 2022. We'll be very active in the coming weeks and months, focusing on rapid execution, building our expertise to launch a commercial product and leveraging the integrated capabilities we've built to enable delivery of our current trials as well as move beyond our existing pipeline. I want to take this opportunity to once again thank James for everything he has done for Adaptimmune and for the field over the last 20 years.

And with that, I'll turn the call open for questions. Operator?

================================================================================

Questions and Answers

--------------------------------------------------------------------------------

Operator [1]

--------------------------------------------------------------------------------

(Operator Instructions) Our first question is from Peter Lawson of SunTrust Robinson Humphrey.

--------------------------------------------------------------------------------

Waleed Abdel-Naby, SunTrust Robinson Humphrey, Inc., Research Division - Research Analyst [2]

--------------------------------------------------------------------------------

This is Waleed, on for Peter Lawson. Could you please just provide a bit more color on the changes to the protocol that was made for the ADP-A2M4 and ADP-A2M10 trials?

--------------------------------------------------------------------------------

Adrian Rawcliffe, Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer [3]

--------------------------------------------------------------------------------

Certainly. Rafael?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [4]

--------------------------------------------------------------------------------

Yes. So immediately, after this event, we changed the conditioning regimen for the patients that were lined up for treatment. So we lowered the cyclophosphamide dose to 600 milligrams per meter square per day times 3, which is the previous dose that we have been using. That now has been incorporated into all our protocols except for the AFP protocol, which has a much lower dose anyway. But all our M10 and M4 protocols now have 600 milligrams per meter square per day x3 of cyclophosphamide, with fludarabine remaining the same. We've made some changes to the inclusion criteria. So patients now have to have a better bone marrow function to enter the study. We've done also some changes in the creatinine clearance, and we've put a maximum age for entry into the study. And because of the stroke, we are excluding patients that have any history of any type of cerebrovascular disease. There are some preclinical experiments that we're doing also to complement the studies. And as I said before, we've been in discussion with FDA to relate these changes. And the studies have continued with all these amendments having been made already.

--------------------------------------------------------------------------------

Waleed Abdel-Naby, SunTrust Robinson Humphrey, Inc., Research Division - Research Analyst [5]

--------------------------------------------------------------------------------

Great. That's really helpful. And just a little bit more on the expected clinical updates upcoming at ESMO. What can we expect to see in the data? How different will it be from the previous update in synovial sarcoma?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [6]

--------------------------------------------------------------------------------

Well, I can't really say how different it will be. Obviously, we will wait to see the results. I can say that we have continued to treat patients. And actually, our accrual has been quite robust. We've treated some patients with MRCLS, but the majority of them have synovial sarcoma. I would just simply say qualitatively that the pattern of tumor shrinkage continues.

--------------------------------------------------------------------------------

Operator [7]

--------------------------------------------------------------------------------

Next question is from the line of Michael Schmidt from Guggenheim Securities.

--------------------------------------------------------------------------------

Kelsey Beatrice Goodwin, Guggenheim Securities, LLC, Research Division - Associate [8]

--------------------------------------------------------------------------------

This is Kelsey, on for Michael. I think we're just -- we're a little -- we're wondering kind of there's been a little bit of disappointment among investors in terms of the progress for the whole TCR category, I guess, especially compared to CAR-T. I guess, what kind of gives you confidence that there is light at the end of the tunnel? And maybe, is there any plans to shift gears a little bit more from shared antigens to neoantigens or perhaps using TCRs that target several different antigens and putting them in some sort of combination?

--------------------------------------------------------------------------------

Adrian Rawcliffe, Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer [9]

--------------------------------------------------------------------------------

Yes. So I think we understand the comment as regard to the TCR field. But I think the data that we showed in May clearly underscores that TCR targeted T-cells can be effective against solid tumors under certain circumstances and just underline that the response data in sarcoma, that was the basis for us initiating the SPEARHEAD-1 trial, which has just started.

And then secondly, the activity that we saw across tumor types, which, although insufficient to enable us to progress forward on any one of those indications, I think, does give us confidence that with the second-gen approaches that we've outlined the radiation sub-study and the SURPASS study, that there is a path forward to derive medicines that have real benefit to patients and that are developable into products. So I think that's our focus. Now I did also mention during my comments that the capabilities that we've built as a company, I think, give us a real prime seat at the table to think about what the world of cell therapy looks like as we go forward. And if you look at the things that we're already doing to branch out beyond the SPEAR T-cell platform that is our first platform and the basis of our pipeline to date, I think I'll just refer you to things like the allogeneic platform that we talked about at ASGCT and our willingness to embrace that, and that's a broad platform that goes well beyond, obviously TCR T-cell therapies. So I think as a cell therapy company, we have a pipeline, we have a product, and we have the opportunity to go beyond that, and that's all we're saying at this point in time.

--------------------------------------------------------------------------------

Kelsey Beatrice Goodwin, Guggenheim Securities, LLC, Research Division - Associate [10]

--------------------------------------------------------------------------------

Okay. Great. That was really helpful. And then just one more, if I can. I guess, in terms of the responses kind of being clustered in synovial sarcoma across both MAGE-A4 and then also NY-ESO, I guess, what is it do you think that's making synovial sarcoma kind of be the one that's rising to the top? And how do you kind of see the positioning of MAGE-A4 versus NY-ESO?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [11]

--------------------------------------------------------------------------------

So this is Rafael. The question of why this tumor is susceptible to TCR, obviously, it's one that we ourselves wonder too. I think this is a tumor that's very poorly immunogenic. There are hardly any antigens or neoantigens rather. It's the result of a translocation, which triggers the expression of this cancer/testis antigens. They're generally expressed diffusely in every cell and generally at high level. So the target is much more abundant than it is in other tumors. So that may be one of the factors. The other is again because the tumors are not inflamed, the tumor microenvironment is essentially devoid of suppressive element. And so T-cells may have the opportunity to traffic and cause cytotoxicity unimpeded. And as you know, checkpoint inhibitors don't tend to work very well in these tumors because they are really very few, if any, TILs that can exert antitumor activity. So I think it's probably a combination of target expression and density together with a favorable microenvironment that makes synovial sarcoma and MRCLS more ideal for this technology. And the question is, how do we make epithelial tumors more like a sarcoma environment, making improvements to TCRs going forward.

--------------------------------------------------------------------------------

Kelsey Beatrice Goodwin, Guggenheim Securities, LLC, Research Division - Associate [12]

--------------------------------------------------------------------------------

Okay. Great. And congrats again Adrian and Rafael. Good luck on your next endeavor.

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [13]

--------------------------------------------------------------------------------

Thank you.

--------------------------------------------------------------------------------

Operator [14]

--------------------------------------------------------------------------------

Our next question is from the line of Marc Frahm from Cowen.

--------------------------------------------------------------------------------

Marc Alan Frahm, Cowen and Company, LLC, Research Division - VP [15]

--------------------------------------------------------------------------------

Rafael, can you give a little bit more detail on the neurotoxicity that was seen in the stroke? And just kind of the timing of them? And why you're confident that the stroke wasn't related to neurotoxicity?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [16]

--------------------------------------------------------------------------------

So this is a patient with ovarian cancer, who developed neurotox approximately a week after infusion. It was mostly manifested by confusion, patient not following commands, et cetera. She had multiple CT scans that showed no evidence of cerebral edema, and she was treated first with anti-IL-6 agents and then with steroids. She was a 70-year-old woman. She had other morbidities including atrial fibrillation. And then she developed a stroke, so her neurologic exam worsened, and she was found to have evidence of -- on physical exam of cerebrovascular agent -- accident, and she had a CAT scan that showed multifocal ischemic areas. And the family opted for hospice care. So we think they are 2 distinct events that there were a series of CAT scans during the neurotox that just showed some changes consistent with neurotoxicity, but no edema. And then when she worsened on physical exam, her CAT scan was very different again showing multiple infarcts. So that's -- obviously, atrial fibrillation can predispose patients to multifocal watershed infarcts, which is what she had, but we can't tell for sure whether that was the cause or there was any other cause for the stroke. But that was the clinical evolution of this patient.

--------------------------------------------------------------------------------

Marc Alan Frahm, Cowen and Company, LLC, Research Division - VP [17]

--------------------------------------------------------------------------------

Okay. Great. Thanks for those details. And then maybe just thinking about the switching back to a lower dose of cyclophosphamide, can you remind -- I mean, the conditioning regimen changed a few times here in the dose escalation period. But can you just remind us using this regimen that you're using moving forward, how many patients were treated in the kind of cohort that you've given us the data from? What was the response rate within that subset of patients?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [18]

--------------------------------------------------------------------------------

Yes. Actually, the majority of the patients that we reported on in May were treated with 600 milligrams per meter x3. So I think we started treating after May, and we treated a couple of patients only at 1,800 milligrams. And so the activity at that time was with the lower dose of cyclophosphamide. In the NY-ESO trial, in the first cohort, the chemotherapy regimen was the 1,800 milligrams regimen with 4 days of fludarabine and it was really well tolerated. And in the past, NCI had done a study again with high-dose chemotherapy as a preparative regimen. And again, they didn't report any fatal pancytopenic events. So we had data that T-cell, our gamma-chain cytokines increase with the depth of lymphodepletion. And we wanted to, given the safety that we had observed before, try to maximize IL-15 and IL-7 secretion to increase proliferation. And so that's why we increased to 1,800 milligrams. So the answer to the question is that we have data of positive benefit-risk with the regimen that we've reverted to, and we believe it's safer. And patients have recovered well. And just to end the commentary, the patient with lung cancer, the first patient I referred to that had pancytopenia had 2 transplants. The first was with the lower dose of cyclophosphamide and he recovered fairly well. He almost had a partial response. And the decision was to re-treat him with a higher dose of lymphodepletion, and he did attain a partial response, but his marrow didn't recover. So I think again we have evidence that 600 milligrams is safe and that's how we are proceeding.

--------------------------------------------------------------------------------

Marc Alan Frahm, Cowen and Company, LLC, Research Division - VP [19]

--------------------------------------------------------------------------------

Okay. Do we -- the person that you're talking about there that got to a partial response, but the marrow didn't recover, is that the sarcoma patient or was that the lung cancer?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [20]

--------------------------------------------------------------------------------

The lung cancer patient.

--------------------------------------------------------------------------------

Operator [21]

--------------------------------------------------------------------------------

Our next question is from Mohit Bansal from Citi.

--------------------------------------------------------------------------------

Keith Tapper, [22]

--------------------------------------------------------------------------------

This is Keith, on for Mohit. I think a lot of my questions are answered, but I just want to know if the changes to the protocol are going to impact the timing or the data for the future studies? And then secondly, on developing the allogeneic program, are you looking at this as a long-term option? Or could you see autologous replacing it once manufacturing and access improve, however, significantly?

--------------------------------------------------------------------------------

Adrian Rawcliffe, Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer [23]

--------------------------------------------------------------------------------

So on the recruitment, we don't anticipate significant impact on the timing of recruitment of the trials based on the changes. On the allogeneic option, as you've said, this is a longer-term project, but -- and it's not known exactly what the profile of an allogeneic product will look like relative to an autologous product. And I think the autologous product represents also the most advanced pipeline. And therefore, I think the focus of the development organization, as we've talked about before, both with SPEARHEAD-1 trial and with the study is to convert the activity that we've seen with our first-generation product into responses and opportunities for further product development there. The allogeneic program we mentioned because we think is very exciting. It is further behind, but we do actually feel in the world of stem cell-derived allogeneic programs, we are amongst the most advanced of those programs, and the opportunity to have a homogenous product off the shelf is obviously fairly, fairly attractive for us.

--------------------------------------------------------------------------------

Operator [24]

--------------------------------------------------------------------------------

Our next question is from Jonathan Chang of SVB Leerink.

--------------------------------------------------------------------------------

Wei Ji Chang, SVB Leerink LLC, Research Division - MD of Emerging Oncology & Senior Research Analyst [25]

--------------------------------------------------------------------------------

First question, can you provide more color on the patient deaths that were deemed treatment-related, and talk about your reasons for confidence that changes to the lymphodepletion regimen that will suffice to avoid this issue moving forward?

--------------------------------------------------------------------------------

Adrian Rawcliffe, Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer [26]

--------------------------------------------------------------------------------

Thanks, Jon. I'll ask Rafael to deal with that. But maybe just to say that the pancytopenia, we think, is pretty clearly related to the cyclophosphamide dosing. And is that -- that's the piece that we think is sort of treatment related, but not obviously, T-cell related. And then on the second point, the -- as Rafael went through, the stroke is, we do not believe, related to treatment. So Rafael, do you want to comment further on that?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [27]

--------------------------------------------------------------------------------

No. I mean, I think I've said this before. These patients were relatively older than the average patient that we treat. There was one patient with sarcoma, another -- and the other 2 had epithelial tumors, ovarian and lung. And the sarcoma patient had received high-dose cyclophosphamide prior to conditioning and that's because she was progressing and the physician felt that he could not wait. And so right after high-dose cyclophosphamide, then she received the conditioning. So that may have contributed as well. The fact that she had been treated with a very myelosuppressive regimen right before lymphodepletion. And the second patient, as I mentioned before, had 2 transplants in the span of 7 months. So we really think that this is due to chemotherapy. We obviously have a scientific review committee that looked at all these cases very carefully. And we added some experts in bone marrow transplant to review the cases as well. And that was the conclusion. And the recommendation to lower to 600 milligrams was backed up by data that we had from the previous sarcoma cohort and the previous expansion cohort of M4 and M10, where we have shown no evidence of prolonged pancytopenia. Patients do get cytopenias, but they recover. So that's what I can say based on the data we have.

--------------------------------------------------------------------------------

Wei Ji Chang, SVB Leerink LLC, Research Division - MD of Emerging Oncology & Senior Research Analyst [28]

--------------------------------------------------------------------------------

Got it. And then just one more question. Should we expect an update later this year from the MAGE-A4, A10 studies beyond the A4 synovial sarcoma presentation at ESMO?

--------------------------------------------------------------------------------

Adrian Rawcliffe, Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer [29]

--------------------------------------------------------------------------------

So we are -- as we talked about, we are closing the A10 study. I think we will update on the A4 study, but it may not happen in the remainder of this year. It may happen when we have reasonable data to be able to communicate.

--------------------------------------------------------------------------------

Operator [30]

--------------------------------------------------------------------------------

Our next question is from Jim Birchenough from Wells Fargo.

--------------------------------------------------------------------------------

James William Birchenough, Wells Fargo Securities, LLC, Research Division - MD and Senior Biotechnology Analyst [31]

--------------------------------------------------------------------------------

Thanks for all the detail on the studies. Just a question on the inclusion and exclusion criteria in the amended protocol. What impact does that have on your ultimate addressable patient population when you exclude certain creatinine clearance levels when you consider bone marrow reserve, age, some of these other factors? By how much does that shrink the addressable market, have you looked at that?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [32]

--------------------------------------------------------------------------------

We've looked at each one individually. Obviously, sarcoma is a disease of younger patients. So there are very few patients in their 70s that have synovial sarcoma. So I think that's really not much of a factor. The rest of the factors, the bone marrow criteria, although they are strengthened, there's still within the realm of what you would see in Phase I study. And the same with creatinine clearance, before it was fairly permissive because we would just suggest the dose of fludarabine. And I just want to make a comment that the label of a product doesn't necessarily reflect inclusion criteria. So I doubt that if this product gets approved, all the details would be in the indication or the selection. It's oftentimes independent of how the patients were selected. But overall, these are relatively minor changes that won't affect the recruitment rate significantly at all.

--------------------------------------------------------------------------------

James William Birchenough, Wells Fargo Securities, LLC, Research Division - MD and Senior Biotechnology Analyst [33]

--------------------------------------------------------------------------------

And then, Rafael, I just want to make sure I understood the comments just on your dialogue with FDA around the protocol modifications. Are you through those discussions and confident that this has been brought by FDA? Is there still any formal feedback you need from them? Just want to assess if there's any further risk to additional modifications of the protocol or is FDA in full agreement with this?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [34]

--------------------------------------------------------------------------------

Obviously, most of the discussions were early on, acknowledging our communications and asking specific questions, which we were able to address fairly quickly. We came up with changes in the protocol. They wanted to see them, obviously, and we changed the protocol very fast. I think our last communication has been probably almost 3 weeks ago. Obviously, we don't know if FDA is going to come back with other questions or changes. But as of today, the trials continue. We have, as I think I alluded to before, in the set of measures that we would undertake have outlined that we will look again at bone marrow precursors in vitro and the effect of our TCRs, but that data will take a little bit longer. And as soon as it's ready, it will be submitted to FDA. But as I said, the clinical discussions, the last interaction was some time ago. So you never know. But for now, we feel like we satisfied their queries.

--------------------------------------------------------------------------------

James William Birchenough, Wells Fargo Securities, LLC, Research Division - MD and Senior Biotechnology Analyst [35]

--------------------------------------------------------------------------------

And then just maybe finally on this topic. It sounds like you're pretty confident that the thrombocytopenia is related to cyclophosphamide, but have you also excluded T-cell-related effects on the platelets, whether it's through some sort of cytokine release phenomenon or a direct effect of the SPEAR T-cells?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [36]

--------------------------------------------------------------------------------

Yes. The cytopenias were trilineage. So it wasn't just platelets, it was white cells and red cells, so the patient became transfusion-dependent. The question is excellent in terms of how can you exclude a role of the TCR. And that's what these in vitro studies are supposed to do. We do it obviously in bone marrow, but unfractionated bone marrow by stem cells and other intermediate precursors, which may have been overlooked if one does it in whole marrow. So we've done tens of this, and we are doing more. But it has been seen with NY-ESO in the past. It has been seen with M10, which is, as I said, before the lung cancer patient was treated with M10 and the sarcoma patient was treated with M4. Aplastic anemia has been seen with TILs, that's very well described. So the thinking is that it's probably due to the conditioning, and ruling out completely the effect of T-cells is difficult because you have to prove a negative. But the fact that it occurs across multiple TCRs and even other modalities and it occurs in patients that get high doses of alkylators suggest that it's more the conditioning the culprit than an immune response.

--------------------------------------------------------------------------------

James William Birchenough, Wells Fargo Securities, LLC, Research Division - MD and Senior Biotechnology Analyst [37]

--------------------------------------------------------------------------------

Got it. And then just maybe one final broader question and just on the SURPASS study. Just wondering what you're looking to see in that next-gen A4 study, whether it's enhanced activity in synovial sarcoma or broader activity into other tumor types? Just wondering what the goal or the expectation is there? When we might see SURPASS data? And then separately, if you could just comment on your neoantigen strategy, if there's a certain neoantigen family you might look at or when we might get more details on a new antigen strategy, if you have one?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [38]

--------------------------------------------------------------------------------

So in terms of SURPASS, so this is a study where the same M4 TCR is delivered together with CD8 alpha. So the intention of this manipulation is to, one, provide CD8 as a coreceptor for Class 1 TCR to CD4 cells. So CD4 cells obviously don't express CD8 and their binding is weak. And although they can kill, they do so at a lower rate and they essentially disappear when you look at persistent, long term. So what we've shown is that CD4 cells are able to kill just as well as CD8 cells when they contain the CD8 alpha molecule. And so in effect, we will increase the number of cytotoxic cells. And sometimes, the ratio of CD4/CD8 is in favor of CD4. That's just -- it's a bit random and it depends on -- among other factors on the starting product. So in a way, it could be seen simplistically as a higher dose because all the cells would be functional, all the transduced cells will be functional. In addition, and I think, at least for me, more importantly, these cells because they bind the MHC Class I and they stabilize and they kill, they are activated, and they expand, and they are able to deliver their CD4 function, including providing helper cell activation, interacting with dendritic cells, which we've shown dendritic cells cytokines increasing in the setting of co-cultures of these cells. And so all of this should lead to antigenic spread. That's difficult to prove in vitro, but I think the fact that you get enhanced activity of APCs when the CD4 cells are transduced with the next-generation CD8 alpha-bearing TCR, it's actually quite positive. So we think we're going to get a more potent immune response, if you will, where CD4s will be engaged. And perhaps, there will be more antigenic spread and maybe even humoral response. And we are developing assays to measure all of that in our patients. So there will be translational set of studies to help us understand how it works. In terms of neoantigens, I don't think we've disclosed the next program. And -- but all I can say is that we do have programs ongoing that relate to this field. And in due course, we will announce them.

--------------------------------------------------------------------------------

Adrian Rawcliffe, Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer [39]

--------------------------------------------------------------------------------

And then just lastly, just to pick up on, you asked about when the first data would be, and we've confirmed the first data from the SURPASS study, we're anticipating in the first half of 2020.

--------------------------------------------------------------------------------

Operator [40]

--------------------------------------------------------------------------------

Our next question is from Tony Butler from Roth Capital Partners.

--------------------------------------------------------------------------------

Charles Anthony Butler, Roth Capital Partners, LLC, Research Division - MD, Senior Equity Analyst & Head of Biotechnology Research [41]

--------------------------------------------------------------------------------

2 questions. First, Adrian, when you announced -- and my apologies if you mentioned this. I got on a bit late. But if and when you announced the interim futility analysis associated with SPEARHEAD, and I recognize it's 3 responses out of the first 15 patients. But obviously, this morning, you've had a lot of questions around the cyclophosphamide challenges, et cetera, and side effects, we can go on and on. The question really is, what -- how will you do that? Will you just say we passed the futility analysis or would you give some incremental additional information around those first 15 patients? That's question 1. And then question 2, Rafael, I am always intrigued by the notion to create additional opportunities for T-cell penetration. It's clearly true in the MD Anderson radiation trial. So I recognize you're giving 7 grays to a patient. They then undergo lymphodepletion, which I am assuming is the same lymphodepletion we've been discussing today. And then they get cells. Is that correct? And then do they go through subsequent ramp? I just would appreciate you outlining that just a little bit because it's a very interesting trial.

--------------------------------------------------------------------------------

Adrian Rawcliffe, Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer [42]

--------------------------------------------------------------------------------

Thanks, Tony. So just to pick up on the first one, the 3 responses is the critical piece. The 15 patients would obviously give you a rate of something like 20% response rate. Clearly, given the patients that we've dosed and seen to date, we are anticipating that 3 responses might occur in something less than -- fewer than 15 patients. And -- but you're right, at that point in time, we will likely just announce that we are -- we have completed the analysis and the study progresses as opposed to giving any further data, acknowledging that this is a trial, which hopefully we will be using at some point to register the product. Rafael, do you want to talk about the next question, the use of radiation sub-study?

--------------------------------------------------------------------------------

Rafael Amado, Adaptimmune Therapeutics plc - President of Research & Development [43]

--------------------------------------------------------------------------------

Yes, sure. So the patient will receive low-dose radiotherapy to selected lesions during the lymphodepletion days. So the lymphodepletion is given over 4 days and they will go to the radiation suite and get 7 grays as you mentioned, which is a sublethal dose to selected lesions. And how the lesions will be selected will be essentially at the discretion of a radiation oncologist. Not all the lesions will be radiated, some will, somewhat won't. And the idea there is to see whether there's differential response between them and also whether there's differential trafficking of our T-cells to the various metastases. And this is based on observations from the checkpoint literature. It's actually being very well documented that low-dose radiation can restore responsiveness to checkpoint inhibitors in patients that are refractory and also from animal model world that was published by the Memorial group actually using CARs and showing the same phenomenon of increased cytotoxicity with CARs in lesions that were irradiated. So we're pretty excited about this study. I think -- and also the fact that we could build it as a sub-study gave us the opportunity of launching it quickly. And it's already open, and we should get information that will help us both with responses, but also with translational data, which is -- it seems pretty exciting for us to learn how the TCRs work.

--------------------------------------------------------------------------------

Operator [44]

--------------------------------------------------------------------------------

Thank you, and now I would like to turn the call over back to Adrian Rawcliffe. Adrian?

--------------------------------------------------------------------------------

Adrian Rawcliffe, Adaptimmune Therapeutics plc - CFO & Principal Accounting Officer [45]

--------------------------------------------------------------------------------

Thank you, and thanks everyone for your continued interest and support of the company. We look forward to updating you as we progress forward to bring our SPEAR T-cells to patients with cancer. And with that, we'll close the call. Thank you.

--------------------------------------------------------------------------------

Operator [46]

--------------------------------------------------------------------------------

This concludes today's conference call. Thank you all for attending. You may now disconnect.