Adaptimmune Therapeutics PLC (ADAP) 2016 Q3 法說會逐字稿

Good day and welcome to the Q3 2016 Adaptimmune Earnings conference call and business update. Today's conference is being recorded.

At this time, I would like to turn the conference over to Mr. Will Roberts. Please go ahead, sir.

Thank you, Anna. Good morning and welcome to Adaptimmune's conference call to discuss our third quarter 2016 financial results and other business updates. As a reminder, today's conference call will contain forward-looking statements. These statements relate to future events or the Company's financial performance, and the listener is cautioned not to rely solely on these forward-looking statements. Such statements are subject to certain risk and uncertainties which could cause actual results to differ materially from any future results expressed in or implied by such statements, especially those inherent in the process of discovering and developing our therapeutic candidates and those set out in our filings with the SEC.

With me on the call this morning and participating in the prepared section of the call are James Noble, our Chief Executive Officer; and Adrian Rawcliffe, our Chief Financial Officer. Rafael Amado, our Chief Medical Officer; Gwen Binder-Scholl, our Chief Technology Officer; and Helen Tayton-Martin, our Chief Operating Officer, will be here available for Q&A after the prepared portion. This call is expected to last approximately one hour.

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

Thanks, Will. Good morning, everyone, and thank you for joining us. We plan to cover a number of topics on the call today, including updates on our recent business enhancements, progress across our clinical and preclinical programs, and our financial results for the quarter.

Since our last update, we have made excellent progress and are now in a period of strong momentum across the business. First, we were very pleased to announce yesterday that the FDA has removed the partial clinical hold on our planned trial of NY-ESO SPEAR T-cells in myxoid/round-cell liposarcoma or MRCLS. We plan to initiate a pilot MRCLS trial and start screening patients around the yearend as previously guided.

I want to reiterate that this was a partial hold that only affected our MRCLS registration study protocol. We have made good progress in many other studies in the interim. And this partial hold was not due to concerns regarding safety in this trial that had not yet started, nor were there any concerns regarding the planned preconditioning regimen with cyclophosphamide and fludarabine.

The CMC requests underpinning the partial hold stemmed primarily from the fact that we are in the process of evolving our manufacturing from an academically-derived process, which we call 1.0, to a commercial-ready process, which we call 1.5. The original MRCLS protocol was going to be the first to utilize product from this new process 1.5.

In short, the FDA asked, in the context to a registration trial, for more data regarding our switch from 1.0 to 1.5, including comparability. Because we did not want to delay initiation of this trial in MRCLS patients, we changed this to a pilot study using our current manufacturing process 1.0 for supply as we worked to finalize our commercial-ready process to supply all future registration studies.

The original MRCLS protocol was designed to be a registration study and included a futility analysis to be conducted with the first 13 patients. If futility was not met, then enrollment would proceed to a maximum of 35 patients. We have now de-coupled the originally proposed registration study into two separate studies so that we can start right away. We will commence with a pilot study in up to 15 patients to assess preliminary safety and efficacy, which is not unlike the futility phase of the original protocol.

Data from this pilot study will then inform a planned registration study. As I confirmed earlier, we expect to start screening patients for the pilot study shortly. Given the significance of MRCLS with the patients impacted by this rare cancer, our goal is to move this program towards a registration study as expeditiously as possible. The timing of initiation of the planned MRCLS registration study will depend on the pilot, and the de-coupling of the pilot from the registration study will ensure that comparability data are available to support the planned registration study.

With respect to business development over the last quarter, as leaders in the field of T-cell cancer immunotherapy, we have sorted our strategic partnerships to assess all potential avenues to further advance our technology. As such, we have formed two partnerships in recent weeks. First, we entered into a multi-year alliance with the University of Texas MD Anderson Cancer Center to advance the development of our cancer immunotherapies. And secondly, we announced a clinical trial collaboration to assess our NY-ESO SPEAR T-cell therapy alone and in combination with KEYTRUDA, Merck's PD-1 inhibitor, in patients with multiple myeloma. This study is planned for initiation in the first half of 2017.

Under this agreement, Merck will provide drug for the study, free of charge, and Adaptimmune will conduct the trial with the company's coordinating activities through a joint development committee. And depending on the outcome, we will have the opportunity to expand this relationship further into additional stages of development.

You may have noticed there have been several changes to our board announced over the past six months, including transitioning to a new chairman at the end of 2016. These changes are reflective of the continued evolution of Adaptimmune as a public Company with three new independent directors joining the board in recent months. At the same time, we have announced the departure of two board members who also served on the board of Immunocore, reflecting our growing independence from our sister company.

This evolution towards independence is further underlined by the mutual decision to end the target identification collaboration between the two companies because we have now established our own capability to identify new Adaptimmune targets. We have had a long and productive collaboration with Immunocore with a significant joint target database to which we will have full access moving forward. We will continue to jointly own IP surrounding the technology, and we'll continue to collaborate and prosecute this IP with Immunocore.

Moving on now to our ongoing clinical work, I would like to briefly cover the importance of the preconditioning regimen across our trials. We have convincing data showing that fludarabine is required as part of our preconditioning regimen for optimal cell expansion and activity. And I want to reassure you that we have not seen the type or severity of neurological toxicities in the presence of fludarabine that have been reported in some studies of CAR-Ts. Thus far, this is consistent with the generally better tolerability profile overall of our NY-ESO SPEAR T-cell therapy as compared o CD19 CAR-T, including a much lower incidence of serious cytokine-release syndrome. As such, all current and future protocols for our trials will include fludarabine in combination with cyclophosphamide for preconditioning, generally at similar doses to those used by peers in the CAR-T space.

On to other preclinical and clinical updates. First and foremost, our wholly-owned pipeline is becoming an increasingly visible element of our business. We recently initiated MD Anderson as the first site in a triple tumor study of MAGE-A10 SPEAR T-cell therapy in patients with urothelial, melanoma, or head and neck cancers. Our MAGE-A10 study in non-small cell lung cancer is also open for recruitment, and we expect to see data from both of these studies in 2017.

Further, we continue to expect to initiate enrollment in the first study of AFP SPEAR T-cell therapy in the first half of 2017. And the R&D for our MAGE-A4 SPEAR T-cell submission remains on track for early 2017.

Secondly, we announced at ESMO that we had initiated dosing with our NY-ESO SPEAR T-cell therapy in Cohort 4 of our synovial sarcoma program, utilizing the modified fludarabine and cyclophosphamide regimen. Encouragingly, we continue to experience strong interest in the study and have already enrolled a majority of the patients for this cohort, and we expect to begin registration studies in this indication in the second half of 2017.

Thirdly, we announced that the amended protocol for evaluating NY-ESO in ovarian cancer patients is now open to enrollment with the same modified fludarabine and cyclophosphamide preconditioning regimen as synovial sarcoma Cohort 4. Fourthly, enrollment is also now underway in our study of our NY-ESO SPEAR T-cell in non-small cell lung cancer. And finally, there will be an update on the NY-ESO sarcoma study at CTOS tomorrow included or updated data showing an encouraging increase in median survival in Cohort 1.

Moving on to manufacturing. Ensuring a long-term supply of our SPEAR T-cell therapies remains a priority, and we have continued to make good progress in that regard. First, I can confirm that we anticipate the opening of our own manufacturing facility in the Philadelphia Navy Yard technology center around the middle of 2017. When all modules are built out, this facility will have the potential to produce therapies for up to 1,200 patients per year with an initial capacity of around 300 to 400 doses.

Secondly, we announced a new five-year strategic manufacturing supply agreement with PCT, and we have also initiated a relationship with the European contract manufacturer, MaSTherCell. Once our own manufacturing facility is on line, these partnerships will augment our internal manufacturing capabilities.

Lastly, we have made good progress in moving from the academically-derived manufacturing process 1.0 to our commercial-ready process 1.5. And as I discussed earlier, we have an agreed-upon plan with the FDA to move forward with this process to future registration studies, and so good progress and momentum across the organization.

And with that, I'll turn the call over to Adrian for his review of our third quarter financial results. Adrian?

Thanks, James, and good morning, everybody. As you saw from this morning's release, I'm pleased to say that we closed our 2016 third quarter with nearly $188 million in terms of liquidity. This is a non-GAAP measure comprising cash, cash equivalents, and short-term investments. So we remain well-capitalized, and our guidance has not changed in that we believe that at currently forecast spend levels this cash should last us into mid-2018.

Let's touch briefly on the financial highlights for the third quarter of 2016. Our revenue, comprised primarily of payments under the GSK agreement, was $2.4 million for the third quarter 2016 compared with $4.9 million in the same period in 2015. As discussed previously, our revenue will continue to be variable based on the achievement and recognition of milestones, which you will remember are designed to offset the costs associated with the NY-ESO program and with other elements of the collaboration.

Regarding our R&D expenses, with progress in our pipeline comes the need for controlled investments into ongoing and planned clinical studies, into our preclinical activities to identify new targets and deliver new INDs from 2017 onwards, and into the talented people performing the work. As such, our R&D expenses were $15.6 million for the third quarter of 2016 compared to $8.9 million for the same period in 2015.

The increase in general and administrative expenses period-over-period related almost entirely to increased personnel costs as we invested appropriately to ensure we are staffed to execute our business plan and deliver our results. These were $5.4 million for the third quarter of 2016 compared to $4.4 million for the comparable 2015 quarter.

All in, we reported an operating loss for the third quarter of $18.6 million, which, after other expenses and taxes, gets us to a net loss of $18.5 million. On a per ordinary share basis, this translates to a loss of $0.04 per ordinary share for the third quarter of 2016. And on the basis of there are six ordinary shares represented by each ADS, we show a net loss of $0.26 per ADS.

The construction of our new facilities in Philadelphia and in Oxfordshire in the U.K. is making good progress, and we remain on track to occupy both buildings in 2017. The landlords have completed the shell and core construction of both buildings, and we are now fitting out the facility. In Q3, we incurred capital expenditure of $2.8 million, which largely relates to these new facilities and is an increase of $1.6 million compared to Q2 2016.

Finally, we are reiterating our previous guidance. Excluding the effect of any potential new to business development activities, we expect our decrease in total liquidity position for the full year 2016 to be between $80 million and $100 million. We, therefore, expect our total liquidity position at December 31, 2016, to be at least $150 million, and we believe we have funding to date to take us into mid-2018.

With that, I want to turn the call back over to James for some closing comments. James?

Thanks, Adrian. I believe that the work ongoing at Adaptimmune has the potential to improve patient outcomes across a variety of diseases. This potential derives from the caliber of our scientists who are conducting industry-leading science at the forefront of the immuno-oncology revolution, and the outstanding development professionals who are driving forward the manufacturing and clinical aspects of our programs. And I want to thank them for their work and dedication.

Although not without risk, this is a period of exciting progress throughout the Company, thanks to our active engagement in the important new partnerships and to the momentum across our clinical pipeline and manufacturing organization. We will continue to develop our preclinical assets towards filing new INDs each year from 2017 onward and expect to have clinical studies underway with at least four SPEAR T-cell therapies in up to 10 cancers with data from many of these studies in 2017. And we expect to be the first TCR company to enter registration studies for such a therapy.

We are accelerating towards all of our corporate goals, generating important new data in multiple tumor types, building clinical expertise by initiating and conducting clinical studies with new constructs, aggressively bringing new INDs towards the clinic, developing TCRs targeting our broad pipeline of solid tumor targets, and exploring the possibility of enhancing the depth and durability of our affinity-enhanced SPEAR T-cell therapies, utilizing combination and/or second- and third-generation strategies. The remainder of 2016 and 2017 is an important time for us, and we thank you for your continued support.

With that, I'd like to open the call up for questions. Operator?

(Operator Instructions) Our first question comes from the Michael Schmidt from Leerink Partners.

I had one on your manufacturing process; in particular, you mentioned the transition to the version 1.5 process. And I was wondering if you could talk what some of those differences, and in your discussions with the FDA requesting you to show comparability, whether that is limited to DMC features or includes also clinical comparability? Thanks.

So, I'll let Gwen Binder-Scholl, who runs manufacturing, answer that.

Yes. Hi, Michael. Yes. The key differences between the two processes have to do with three areas of the manufacturing. The first is we've incorporated freeze stop in the increases, which provides us with a lot more flexibility in manufacturing scheduling. The second is we simplified the upstream purification of process. So, now it's a single-step enrichment of T-cells. So, we've removed some complicated steps, which enhances our ability and reproducibility of the process. And the final is we've simplified the T-cell media and reduced serum requirements as well. So that has implications both in reducing clean room time and also reducing supply chain risk.

And then your second question was about comparability. And so, all of our comparability studies are in-vitro studies, and we are not doing any clinical -- we have not been required to do any clinical comparability. So, it's all analytical.

And then my other question was around the safety profile of your engineered TCR-based T-cells in general. And, James, you mentioned the potentially better tolerability compared to CAR-T in terms of CRS and neuro tox, and I was wondering what the rationale or the theory is behind that better tolerability? Thank you.

I'll ask Rafael Amado, our CMO, to address those questions, first, on the actual tox we've seen, and then maybe we can discuss some of the reasons behind that.

Yes, Michael. So, in terms of toxicity, we do see the majority of patients having adverse events, which by and large relate to their conditioning. And so, those are all, as you might expect, events that have to do with myelosuppression and complications of chemotherapy that are transient and generally manageable.

When we talk about the specific events that you may see with this cell therapy, CRS, we continue to see lower incidents that have been described with CAR19 products. It's in the high 20%, and we've -- out of 20-plus patients, we saw, I think, a single grade 4 for event. So, most of them are grade 3, and we've learned -- we and others have a learned a lot about the management of CRS and early institution of [undialed] 6 therapy. So, it's becoming something that, I think, the field is managing well and -- but there's no question now that the incidence and severity that we see is lower than what's seen at least with the CAR19. I think that there is a lot of speculation as to what that can be due to -- including tumor bulk, ready access to the target cells, et cetera, which is much higher with CAR19.

In terms of neuro tox, we essentially have seen nothing akin to what's been seen in the CAR19 space. And the speculation for why that can happen -- I mean I think you've heard some of these theories in the past. I don't think anyone knows exactly why CAR19 in ALL and large cell lymphoma and other indications associated with this neurotoxicity. That is very -- I think it's a very well-defined syndrome that we have yet to see in this space and whether it is some target expression in the brain or the brain being a sanctuary for cancer cells through leukemia and some other speculation. I think that still needs to be determined. I don't think it's due to fludarabine as a chemotherapy agent per se because even in our high dose conditioning, we haven't seen that sort of complication. So, I think that's what we can say for now.

Okay, great. Thank you very much.

We'll now take our next question from Peter Lawson from SunTrust Robinson Humphrey.

This is Soumit Roy for Peter Lawson. Congratulations on the great progress. And I might be asking this question a bit of ahead of the data, but trying to understand for the synovial sarcoma patients, how many of them passed the nine-month mark in your study out of, I think, some responding patients because there has been a response to the abstract we saw saying at nine months one of the patients relapsed? And the second one is related to the manufacturing process. How much is it automated or closed system because of this NCI had the problem with the CAR-T contamination related issues? So, we are trying to understand how much of it is semi-automated and that can be averted? Thank you.

So, on the first question, it's slightly awkward because we're actually -- those data are being released including the exact overall survival, the median survival data tomorrow at CTOS, which is in Lisbon. There are two sets of presentations at the moment, one is at SITC, which is obviously here in Washington D.C., in National Harbor; and the second is at CTOS, and we're actually putting the data out there. So, in terms of the median survival and the other data relating to progress on synovial, we are slightly hamstrung to -- all we can say is that we're very encouraged by the increase in the median survival since we last reported it being a year, which was six months ago or so.

And I will let Gwen Binder-Scholl talk about the extent of contamination and automation in manufacturing?

Yes, hi. Thank you for your question. So, when we initially transferred our process over from the University of Pennsylvania to our contract manufacturer, we did close almost all steps of the process. And by the time we get to commercial manufacture, it will be completely closed. We haven't had contamination issues since we transferred this process over to PCT, and there are no concerns regarding contamination in our manufacturing processes. This hasn't been an issue with us. Full stop. Yes.

Thank you.

Our next question comes from Marc Frahm from Cowen and Company.

First, maybe, Rafael, if you could give an update on the enrollment for MAGE-A10. I know last time you mentioned there was a bit of a slowdown because of some failure -- screening failures in adenocarcinoma. And then why the -- and then maybe comment also on why the triple tumor trial also has a 3.3 -- 3 plus 3 design and not just a dose expansion?

Yes. Thanks, Marc. So, let me start with the last question. Because we haven't finished dose-escalation in lung, we have still the triple tumor as a dose-escalation as well. We hope that we can leverage the information that we get between both trials, and maybe be able to move accordingly a bit faster. But they are designed as parallel trial. And, again, we will have the same sort of rules with regard to waiting in between doses.

In terms of approval, with the rest of the triple tumor, that's just getting going at MD Anderson. And we're pretty excited about the collaboration and hope that that's going to be a really helpful alliance for us to assist patients and learn more about this therapy. So, there is lot of enthusiasm at MD Anderson and obviously at Adaptimmune. And so, we hope to see a lot of progress there.

In lung, the evidence of marker-positive disease has remained lower than we thought, again, we've made a strong effort to start screening squamous cell carcinoma patients and that's been going well. Actually, there's a lot of awareness among investigators that marker expression is higher in the sub-type of lung cancer, and we're seeing a lot more squamous cell lung cancer patients coming to screening.

And we are actually finding patients that are positive and getting them through dose-escalation. It's still early days. But we're hopeful that this is going to pick up. We've also, as you can imagine, made planning to increase the number of sites, and we are in the midst of expanding to Europe to adjust to the expression levels that we're seeing.

And then back to NY-ESO, in synovial sarcoma, I think previously you've mentioned trying to get a SPA in place for that pivotal trial. Can you update us on where these negotiations are and maybe where the kind of main points of agreement are that you guys still need to be made?

Yes. So, we have agreed in principle to some key design features of the trial, for instance, the fact that it will be a single arm study, what sort of response level we would consider clinically significant and so on. Obviously, these aren't definitive agreements, but I think we've had really good dialogue with FDA and the signals are positive. We have decided to submit the SPA. We are actively preparing for that, and it will be submitted very shortly.

Okay, thank you.

We will now take our next question from Tony Butler from Guggenheim Securities.

Thanks very much. James, in the original IND for myxoid round cell liposarcoma was the manufacturing at that time for the IND 1.0 and then in between the IND filing and when you begin to enroll patients, that was when the 1.5 manufacturing process change occurred? I'm just trying to understand the timing relative to the IND filing. And then secondly, on the same trial, in the pilot, is -- would there be a futility analysis following the pilot? And is it -- would it be true regardless of the answer to that? Would you just simply need or do you feel you'll need only 20 additional patients to achieve that same max number of around 35 for completion of the registration study? Thank you very much.

Thank you, Tony. So, I'll let Gwen to take the questions on the manufacturing process, and I'll ask Rafael to follow that up with the question on the futility analysis.

Yes. Hi, Tony. That's a very good question actually regarding the manufacturing process and the IND. So, the way our IND is structured is we have all of our NY-ESO studies under one IND. So, when the myxoid study was originally submitted, it was submitted under the IND that still had the process, our original process within the IND. And as we mentioned during the conference call, we're in the process now of submitting the information regarding our updated process 1.5 to the FDA now.

On the clinical design, Tony, or the trial design of this study, so it's up to 15 patients. These are 15 evaluable patients and we obviously hope to be able to make a decision with 10 patients depending on what levels of responses and durability we see.

In terms of what else it would take to potentially get enough data for registration in this indication, we have yet to make those decisions and come up with a plan because it's really going to depend on what we see in the pilot trial. It could very well be that that we then require exactly what you said; another trial that enrolls another 20 patients or so. That's certainly our hope, but we'll have to wait and see what we see from the pilot and what transpires from the FDA discussion.

But we're not expecting a second futility analysis.

No, that's correct.

Yes, because it replaces the futility analysis because essentially it's because we haven't faced the [NY-ESO] patient yet. So we obviously need to see the correct level of signal in the first 15 -- after 15 patients. So it just replaces that.

Yes, but still, James, it would be a quasi go/no-go decision, right, to continue that enrollment? So, by definition, it's kind of one and the same. Is that fair?

Yes, yes, exactly right.

And my other question then was around multiple myeloma, some -- at least some of the CAR-T companies have been using or considering using BCMA as a target. And I'm curious your thoughts around that versus -- and why you still want -- and how you think through the net number of multiple myeloma patients that may be more or less susceptible to NY-ESO TCR, which should be awfully potent and has demonstrated potency, at least previously, in those types of patients. Thanks.

Yes. I mean clearly in the current stage, BCMA looks to be an interesting target. And although there's not a lot of data, the data that existed is promising. It's, I think, early days to know how these technologies are going to play out. We're excited about what we saw in the transplant study. And I think this new trial is designed to get an accurate measurement of what the NY-ESO TCR can do in the absence of myeloablation for transplant, which is an important point for us, as well as what the combination can do to prevent resistance and lengthen durability of response. And I think when it's so early with that technology it's difficult to predict. I think a lot of it is going to boil down to how active both each technology is and how safe they are. And, of course, there are expression differences between the two markers and so on. So I think it's good that there's more than one option out there in myeloma for cell therapy, and we'll just have to see how both evolve.

I think the only thing, Tony, is that we are -- and in fact, there's a place for SITC tomorrow about one of the second generation T-cell products that we've got under investigation. We think it's very important in a generic sense, ignoring the fact that it's multiple myeloma, to find out the impact of either combination therapies or the second generation program. So, today, obviously, we're now talking about KEYTRUDA in multiple myeloma. But then tomorrow, we're talking about second generation, and that these are just the sort of first steps in working out exactly how to increase durability and depth of response across the program so it wouldn't end up only being in multiple myeloma. What you need to do is you need to get a signal first and then to look at the effect of combinations or second generation.

Our next question is from Ying Wang from Bank of America Merrill Lynch.

First of all, can you tell us a little bit about the expected timeline on reporting the Cohort 4 of synovial sarcoma study? And then secondly, I want to follow up again on the non-small cell lung cancer enrollment. Can you tell us how many more new sites have been opened? And the slower enrollment, is that a result of lack of NY-ESO or MAGE-A10 expression or it's because of the competition from other immune checkpoint trials in the centers? And then lastly, in terms of your 1.5 or 2.0 manufacturing, can you talk about whether there is any reduction in manufacturing time. Thank you.

So I'll let Gwen answer the manufacturing question first, and then we'll come back -- I'll ask Rafael to come back on the other two points.

Sure. Yes, thanks, Ying, for your question. So we have not changed the manufacturing time. Right now, we don't feel that the duration of manufacturing is any impediment for us to get the product to the patient reasonable period of time, which right now is four weeks end to end.

We also feel that that time frame of expansion of the T-cells enables us to activate and expand the T-cells in order to achieve our target dose. And that expansion allows us to begin the manufacturing with smaller numbers of T-cells from the patients and also reduces the cost of certain key reagents as well.

So the real changes to the manufacturing -- I think we could probably take for it our current process 1.0 commercially if we needed to. The changes that we're implementing are really meant to reduce the cost of goods and actually increase our manufacturing flexibility and reproducibility. So that's really the core.

Rafael?

Yes. And so, in terms of the lung cancer studies, so the --actually, screening is pretty brisk and is proceeding nicely. So I don't really think that competition is really becoming a big problem. I'm sure there are lots of studies that these centers have with immunotherapy and other products. But they're definitely enthused about these studies. And screening, [as I say,] continued to be quite good and increasing.

In terms of our target number of sites, we are looking to have in or around 17 or so sites, including U.S. and Europe, and we are about halfway there, I would say. And the reason for that is we have two trials. We try to place both trials in the same centers. And we may have other TCRs coming through where lung cancer is one of the indications. So we want to get a good cadre of sites that are experiencing cell therapy to put our products through.

I think that's --

Sarcoma Cohort 4.

Sarcoma Cohort 4 is growing quite well, actually. I think it's kind of a testament to what happens when all the sites come up and running, and also the evidence of activity that's being observed, so. I can't say more than the fact that accrual is currently finished relatively quick. And in terms of data, well, we have to look for responses. We like to look for confirmed responses. So we'll have some data around this by mid next year for sure.

(Operator Instructions) Our next question is from Reni Benjamin from Raymond James.

I guess just remind me, if I'm thinking about this right, but all the studies that are ongoing right now, are you using Version 1.0? And the MRCLS study is the only one that's going to be using 1.5. Is that correct?

Yes, that's correct that all the studies currently are using process 1.0. The intention is to transition over to the process 1.5 as soon as it's available. And it is correct that the MRCLS study would have been -- it would have been the first study using solely process 1.5, and that's still maybe the case in fact.

And so, I guess that leads to my next question. In your discussions with the FDA, as you decide to move to, let's say, pivotal studies for any of the ongoing programs, will you need to conduct an additional pilot study first with the new manufacturing process?

No, so -- so that's a good question. So, that's really the purpose of the comparability studies that we have mentioned today in the call is to show on an in-vitro basis that the processes are comparable. So we would not need to do any clinical bridging or additional clinical testing in order to rule out process 1.5 into the clinical study site.

Yes, there's just one single set of in-vitro comparability studies that are needed, and then that would apply to everything.

And that in-vitro study is -- because I -- correct me if I'm wrong, but in the space, in general, I thought that there is a lot of discussion on how exactly to design these comparability studies. Once you do the in-vitro tests, is that something that then goes back and is discussed with the FDA? Or are you guys pretty much anchored down on what that comparability test is?

Yes, no, you're absolutely right, that this is an area of really active discussion in the field about comparability. But in our specific case, given the specific changes in our manufacturing process, which I described earlier, we have discussed this with the FDA and come to an agreement about what needs to be done. And the basic principles are it's just taking -- the biggest issue is donor to donor variability. So we'll take three donors and just split the apheresis and run both processes.

Got it. Okay.

And that's an agreed-to experiment with the FDA, yes.

Got it. Thank you. And I guess just a little bit of a high level question, do you think there -- do you think or do you have any evidence that the treatment to prior immunotherapies or checkpoints may impact the expression of tumor antigens that your TCR products are targeting? And maybe related to that, have you seen any sort of an escape phenomenon yet in those that are currently being treated by TCRs or loss of response?

Gwen and Rafael? I'll start with Gwen.

Yes, so a lot of this data, Michael, is emerging, and there's been data also recently published like from Toni Ribas's group looking at patients that have been treated with PD-1 blockade and who then have relapsed, and trying to understand the mechanisms of resistance. They have seen loss of HLA or loss of interferon gamma, the JAK-STAT signaling pathway. And so, certainly tumors are clearly -- tumors that have been treated with immunotherapies clearly are adapting to them by reducing their sensitivity to the immune system.

We are trying to do studies in the -- our synovial sarcoma studies, I don't believe that we're releasing the outcome of these studies, although we are preparing a publication. But I can say that we are seeing some similarities as well. We certainly have published in our Nature Medicine paper in multiple myeloma, that loss of the NY-ESO antigen is a mechanism of resistance in a subset of patients. We also have presented that in our synovial sarcoma studies that there are -- there is a patient that has loss of antigen. But I think there are other mechanisms of resistance as well. And so that's really an intense area of focus for the Company right now to understand those mechanisms so that we can leverage that understanding to select the right second gen and combination approaches to improve the depth and durability of responses moving forward.

And the only thing I would add to that is that, again, we don't know really what prior therapy, including immunotherapy, does to antigen expression. There is very little data on that. And as a consequence, we are -- while we're not yet mandating this in every study, we are encouraging and consistently sites are complying with it, to obtain biopsies upfront for screening of antigen so that we know what the most recent phenotype of the tumor is with regard to expression of the target.

Thanks, guys. Congratulations on the progress.

We will now take a follow-on question from Michael Schmidt from Leerink Partners.

I had a question regarding your upcoming survival analysis on the synovial sarcoma study. And I'm just wondering if you could provide some context on what type of median overall survival would be expected in those types of patients that would have been treated the standard of care as opposed to the T-cell therapy. Thank you.

Yes. So, the first thing is this is -- there are three presentations at SITC tomorrow dealing with various aspects, dealing with the second generation, but this is going to be an oral presentation at CTOS tomorrow. And so, it is going to be a general update on the NY-ESO cohort. So, the survival data, again, come from Cohort 1; in other words, the original cohort where we've already published the data on survival. And I'll let Rafael comment on what normal survival might be in the context of these very late-stage synovial sarcoma patients.

Yes, I mean it is somewhat difficult to answer a number because a lot of the series compile multiple histologies, not just synovial. There are some -- more synovial-specific and including a subset of studies like the (inaudible) study and some of the recent products that have been approved like the Lilly product antibody and others.

In general, for patients that have failed ifosfamide and/or doxorubicin, most of the series report survivals in the order of 12 to 14 months. And to try to hone in to these questions, we are looking at the series from our patients that have screened negative and haven't come into our trial to see really what their survival was. Obviously, it's not randomized data, but it's probably going to be one of the best sources that we will have in terms of how patients do with standard [salvage] therapies. And we hope to have that data once we finally report on this pilot study to put our results into context. But for now, I think a year is sort of the benchmark that most people would agree with.

Great. Thank you for the clarification.

Our next question is from Robyn Karnauskas from Citigroup.

Hey, guys, this is [Trevon] for Robyn. She says sorry she can't be on the call. Congratulations on all the progress. I'm looking forward to updates over the next few months. So I had a couple of quick questions. Can you just give us an idea of when in the (inaudible) sarcoma program we might actually see data? I mean you're going to start screening by the end of the year. So when can we expect to see early data? And in the sarcoma program, and I apologize if this question has already been asked before, but what would you need to see in all the cohorts that you're treating and you've treated in order to really feel comfortable going into registration trials?

So, in your last question, are you referring to synovial specifically?

Yes, synovial, yes, yes. Sorry.

Yes, yes. Yes, so I think the kinds of outcomes that we're seeing now of response rates and durability are definitely, I think, results that people judge as clinically significant and even response rates that are lower than that, given that really there are not very many therapies that consistently give responses in these patients. And so our numbers -- tomorrow we will report on this, but the most recent updates that we presented at ESMO and so on are 50% to 60% response rate. So I'd say even responses lower than that, provided that they are durable, are clinically beneficial for these patients who normally get a lot of toxicity from the existing therapies but not very much benefit.

With regard to the MRCLS study and when we will see enough data to be able to report, I think it's difficult to say. There is a lot of excitement on the site to get going. And as I said before and James said before, we are going to start screening hopefully very soon by the end of the year. And, again, it will depend on how quickly the patients come in, and we can't get enough response data to have a meaningful update. It is open label so we can definitely make reports on interim data. My sense is that we will need about a year or so to have meaningful data around this histology. So hopefully we'll have enough to report in 2017, but it would have to be towards the end.

Great. Thank you so much.

As there are no further questions in the queue, I would now like to turn the call back to Mr. James Noble, our CEO, for any additional remarks. Thank you.

Thanks very much for attending the conference and indeed for giving us such an excellent set of questions. It's clear to us that manufacturing is very important, and I think the release of the clinical hold means that we can progress. So we're basically very excited about 2017. We're recruiting very quickly in that Cohort 4. As we've just said, we've got the MD Anderson alongside us for our future programs and we have a clear path forward agreed with the FDA on the manufacturing issue, so we feel very good about the rest of this year and 2017, and we hope to provide some good data updates over the next 12 months. So thank you very much indeed.

Thank you, sir. Ladies and gentlemen, that now concludes today's conference call. Thank you for your participation. You may now disconnect.