Adaptimmune Therapeutics plc (ADAPY) Earnings Call Transcript & Summary

Great. Thank you, everyone, for joining us today. My name is Mohit Bansal, and I'm one of the biotech analysts here at Citi, and I welcome you all for Citi's 15th Annual Biopharma Virtual Conference. And to kick off my sessions in this conference, we have -- we are pleased to have Adaptimmune management team joining us today. We are joined by Gavin Wood, the CFO; John Lunger, the Chief Patient Supply Officer; Mark Dudley, the SVP of Early stage Development, and also Elliot Norry, MD and Chief Medical Officer of the company. Thank you, all of you for joining us today.

Thank you.

Thank you.

Great. So Elliot, this has been a quite eventful year for Adaptimmune. You have seen responses in multiple tumors, which -- outside of synovial sarcoma as well. So just wanted to briefly touch upon your journey this year, the data you have seen so far, if you can briefly touch upon that. And what is in store for us, what we could see from the company coming up for the remainder of the year as well?

So thanks very much, Mohit, and thanks for the opportunity. I'll try and give just a reader's digest version of where we've been, let's say, in the last 9 months as a company and where we think we're headed in the relatively near future. So going back to January and then into end of May, June, around the ASCO conference, we've progressively presented exciting data showing efficacy in solid tumors with our TCR, T-cell receptor platform beyond the sarcoma indication where even prior to January we had seen exciting data. At this point, we've seen responses to our therapies across 6 different tumor types. And we've also seen that across different T-cell receptors. So both the MAGE-A4 directed T-cell receptor as well as the AFP-directed T-cell receptor. With that, we're planning to take our first product to the marketplace in 2022, that being the first generation T-cell receptor directed against MAGE-A4 for the treatment of sarcomas. We do this really across an integrated platform that reaches all the way back into discovery and early research through product development. And then into early phase and then late phase clinical trials and all supported by a manufacturing and patient supply capability that we've really spent the last few years building to the point of being in a position to be ready for a commercial launch in 2022. On top of that, we also have an exciting pipeline and have new products in development, probably highlighted by our allogeneic program or an off-the-shelf T-cell receptor program, which has multiple capabilities but is also sort of highlighted by the ability to introduce HLA independent T-cell receptors and CAR-T type receptors through our partnership with Astellas, which was also announced earlier this year. So I think that at this juncture, we're really focused on, number one, producing the data that we believe we can in our Phase II study in sarcomas in order to support the market launch in 2022 also focused on the development and understanding of further signals in other solid tumors to advance into late stage, including, as we've announced, a plan to investigate gastroesophageal cancers with our next generation or second generation T-cell receptor with CD8 alpha cofactor. And we're also very excited about the potential for the AFP-directed T-cell receptor based on the complete response that we've seen and other indicators of anti-tumor activity. Those are our clinical trial focuses for the short term, and we've decided to use the tumor types where we've seen early evidence of activity. So gastroesophageal cancers, head and neck cancer, bladder cancer and lung cancer, those will be the focuses of our CD8 alpha first-generation T-cell receptor studies going forward. And we're also exploring a combination with PD-1 inhibitors with -- specifically in head and neck Phase II trial. So we've really got a pretty full menu of clinical trials. We continue to focus on being fully integrated and sort of commercial-ready in 2022 with our planned first launch and a robust pipeline with the highlight being the allogenic program.

Got it. This is a very helpful overview. Maybe one related question to that. The Adaptimmune we see today and we have seen data in multiple tumors now has come a long way from in last coupe of -- last 3, 4 years where it took some time for you to actually get to where you are right now. So could you please touch upon the challenges you faced, the -- what you have learned with your early work and early efforts that you are applying now and probably compare to what you were doing before. I mean, it seems like the data are coming pretty quickly. And we are seeing much more than we saw in the last few years?

So I can try to take some of that question and I'll ask maybe Mark can chime in as well. I think that we've used our translational research data to really inform the way that we might -- and our preclinical data to inform what we might take into the clinic. So first of all, it did just take some time to see responses in some other solid tumor types with the MAGE-A4 directed first-generation program. But we had already launched a study with our second-generation program, the CD8 alpha TCR or the SURPASS trial. And we used preclinical information to inform that the CD8 -- the CD4 cells that we -- that were affected by this vector took on killing capabilities. So the helper cells became killer cells, and we saw this in the laboratory. And then when introduced into the clinic, we saw some responses with lower cell doses than we had seen before. We also leveraged our partnership with MD Anderson Cancer Center and the research that they had done in -- with low-dose radiation to try and look at that in combination with our T-cell therapy to improve trafficking of the T-cells. And with that, we saw a response in the first patient treated with melanoma. And then also the direction of combination with PD-1 inhibitor was based on translational information that we saw with sarcoma patients in particular but -- that there was some upregulation of PD-1 with treatment such that this combination might make sense going forward. So those are really the things that we saw from our -- what we learned over the last few years that we've used to take into clinical trials going forward. I don't know, Mark, do you want to add anything to that?

Thanks, Elliot. I think you summarized it pretty well. It's such an exciting time because we're learning so quickly. And I would say the first thing is that Adaptimmune has aspirations to be a fully integrated company. And so one of the things that we learned right off is in synovial sarcoma, the first generation is a really solid therapy and so we moved that forward into a second-generation registration trial. So that was really helpful. But then as Elliot said, the opportunity to continue developing didn't stop. There's -- in cell therapies, there a lot of opportunities, and we've combined the first generation in a combo therapy with an anti-PD-1, that open. We've added -- in a radiation substudy, we added radiation to -- low-dose radiation to tumors. As Elliot mentioned, the first patient responded on that protocol as we report. And then finally, we also put in a second gene, which we call a second-gen construct. And took the MAGE-A4 receptor which was showing responses and amplified those in other indications by including both the CD8 and the CD4 subsets in the response, putting CD8 into the CD4 T-cells makes them not only lytic but also more potent in terms of cytokine and chemokine expression. So there's a lot of opportunities Adaptimmune is really pushing forward in clinical discovery in a lot of those areas.

Very helpful, Mark and Elliot, both. So Mark, maybe one question I have to ask you is that you have some sort of new model where you actually can press your hypothesis very quickly and you can be either fail or be successful very quickly. Can you please elaborate on that? What is that packet? Is that -- I mean, it is pretty good actually from the development point of view because you can -- you know where to invest money faster than you were before?

Well, glad you think so. We are very excited about our capability to rapidly evaluate new products. And I have to say that comes from quite an effort to build platforms. We have an integrated and internal manufacturing platform, which John Lunger can speak about. And we also have a rich research pipeline, which we can delve into. But one of the key areas that I could elaborate on is cell therapy is kind of unique. You get so much data from each patient that you treat. There's recent biomarkers and -- plus each patient is a new lot, you learn quickly about what is working and what's not working. So as an example, all of our T-cell receptor trials have started as dose-escalation trials with safety escalation. Actually, we haven't hit dose-limiting toxicity with any T-cell receptor. But we have seen responses in the MAGE-A4 when we got to around the 5 billion cell dose. And we also saw that with the AFP receptor in hepatocellular carcinoma. The first patient treated with 5.6 billion transduced cells had a response, which we then reported as a complete response. So we were quite excited and surprised when in the second-gen dose-escalation study, where the first cohort was principally for safety, we actually saw responses. And we saw tumor shrinkage in 2 of the 3 patients treated at the lowest cohort. So that's an example about how you can learn things very quickly. We are still trying to evaluate, are evaluating multiple types of translation to understand if these cells are more potent and how they can -- how the dose and the potency relates to tumor regression.

So this is very helpful, actually. Maybe, John, for you, just for the benefit of listeners here, could you please explain what do you mean when you say full integration is important. What is full integration here? And your capabilities, manufacturing capabilities, and if you can talk a little bit about that as well.

Sure. Thank you. So our current manufacturing setup is a mix of internal and external manufacturers, both for the lentiviral vector which delivers a gene as well as the drug product the SPEAR T-cell manufacturing, although our primary source of drug product comes from our facility that we've built in Philadelphia. Manufacturing -- and to answer the question on integration, integration is really about having the process development, analytical development; vector manufacturing, which we have developed our own proprietary viral vector manufacturing process, which we are producing some of the Cell and Gene Therapy Catapult facility in Stevenage; and then finally, the drug product manufacturing and all the way towards supply to the clinical site. So that's what we mean by integrated. And then to Mark's point, when you take the translational capabilities that we have to understand the outcomes at the patient level, understand the manufacturing process, and then quickly make those changes to get into the multiple manufacturing processes that we have in the various trials. So that's integrated. There's a couple of key points, I think, on the manufacturing that are kind of underappreciated in this space. One relates to the reproducibility of the manufacturing process itself. And so we've seen over the last several hundred patients that we've managed to manufacture over the last several years multiple TCRs, multiple tumor types. We've had a very high, north of 90% success rate, the very first time we make those manufacturing batches; in the rare cases where we have to do a remanufacture, I can only think of one-time very early on several years ago where we were unable to dose a patient. So that's the reproducibility side. The second part is process speed. That's what we talk about cycle time from the time we start manufacturing until we release that product back to the patient. And we've seen that drop by about 30% in the last year to around 25 days. So that's one big part of manufacturing and having the capability to do that internally and optimize that quickly is important. And then finally, I just want to talk about scale real quick. We had to scale out and scale up. And then the scale-out is about being able to manage multiple processes, and you've probably heard the phrase that the process is the product. But what that means is as we take the learnings that come out of the early phase group, whether it's different type of media that we need to add or different cell dose or different types of unit operations that we optimize, all of those have to be introduced in a controlled way into the clinic. And if you're doing that yourself, you can manage that much, much more quicker. So that's the scale-out part to manage multiple trials and multiple TCRs. And finally, there's a scale-up. And the scale-up is as you go towards commercial with the sarcoma asset in 2022, the process is fixed. And now it's about just more patients, more geographies. And that's where our facility in the Navy Yard, which has actually some extra space in the building that we're just now starting to do the detailed engineering work on how to scale up for 2022. It gives us the ability to meet that geographic and patient scale.

Got it. And one more question we get a lot is that when you talk about 5 billion cells or 10 billion cells, I mean, how -- we get moved by that? I mean, this is such a big dose. I mean, how big is the dose in terms of manufacturability? Can you please put some context behind this?

Yes. So dose is driven by total cells, and then, of course, the transduction efficiency that you have in terms of getting the gene of interest into the cells. So the dose is the transduced cell dose. We haven't had any real issues to hit around that 5 billion target. There's -- it's a function of how long you grow the cells as well, how many you start with in terms of what you collect from the patient. Typically, when we collect from a patient, we have 1 to 3 aliquots of cells enough to do up to 1 to 3 manufacturing runs even in parallel if we needed to, to hit those doses. So we tend to make everything we get from the patient, and we frankly have not had any issues hitting those higher numbers. In fact, higher than 10 billion occasionally, we can do that, even with material left over from the patient in case we need to do a second run. So we don't have to go back and read for each of the patient.

Got it. Very, very helpful. I'm getting one, an investor question, if I may ask that. So this is related to the lung cancer response. Were you able to confirm that response or can you talk a little bit more about the effort in lung cancer there? Elliot, do you want to take that?

Sure. So we haven't updated the data with respect to lung cancer since May. So what we presented in May would still be the most up-to-date information on lung cancer patients. The -- with respect to the -- that patient had squamous cell lung cancer. And they had a meaningful response that has led us to use that as one of the focuses in our SURPASS study. And we're really focusing on trying to recruit patients with lung cancer into SURPASS so that we can further evaluate whether or not that response is exactly -- it is -- what's the replicability, the response rate that we'll actually see when we put enough patients with lung cancer into the study with a second-generation T-cell receptor, not the first generation. I hope that answers the question.

Got it. It does actually. So in terms of -- so you talk about first generation and second generation. For the benefit of listeners, can you talk -- can you elaborate further on what changes you have made in the second generation versus the first generation, be it safety? Well, like, what it means in terms of efficacy and more importantly safety because TCRs have been -- at least the initial ones were toxic?

I can take that.

Go ahead, Mark.

So the first generation product is the alpha and beta T-cell receptor genes put into T-cells, and that means that they express a new specificity on the surface; second generation to us means that we add a second gene. So we'll try to program the cell function and phenotype. And in this case, we added a CD8 gene. So the specific functioning is relatively unchanged. Even so Adaptimmune has a world-class, probably best-in-class safety -- preclinical safety package. And so we ran the second generation through the preclinical safety package before we introduced it into a clinical trial. With our rapid approach, we were able to see relatively quickly that the second generation had aspects that the first generation is interesting, and we're still pursuing that. Hopefully, we'll be able to report on these results in an upcoming scientific conference.

Got it. And so just staying on this A2M4CD8 program now, I mean you have -- can you talk a little bit about the rationale? So you started with lung cancer, you saw a response there. Could you talk a little bit more about the indications you have selected there, you have lung cancer, you have head and neck, you have bladder cancer. So you have multiple tumors there. And the Phase II plan is to start in 2021. Can you talk a little bit more about the rationale for these indications there? And more importantly, what sort of responses you are looking forward to move into? What is your threshold to move into a bigger Phase III trial or expand the cohort or something like that?

So I can take a first crack at that. So we really use the information from the earlier data to inform where we're going to head with the second-generation CD8 alpha program. It's really the tumor types where we've seen responses where we're heading with that program. So as you know, I mean, the first 2 patients with gastroesophageal junction cancer that we treated with the CD8 alpha second-generation program had responses, evidence of antitumor activity with a 1 billion cell dose. And we thought that this was really remarkable that the first 2 had shown evidence of such significant activity. So it became apparent to us that we really should be planning for a later stage program that looks in detail at this tumor type. The other tumor types, lung cancer, we've mentioned, there was a patient with the confirmed response in the first-generation T-cell receptor program; head and neck cancer, we've seen patients with anti-tumor activity in both the first and second-generation program; and bladder cancer was a little bit more interesting in that there was a patient that had a marked reduction in their target lesion of 67%, a fairly substantial lesion, but that patient wasn't a responder based on RECIST criteria because they had new progression of brain metastases. So although the patient didn't meet criteria for a RECIST response, really, in a Phase I program, we're looking for evidence of anti-tumor activity that's convincing and seeing that 67% reduction was convincing to us. So those 4 tumor types: gastroesophageal cancers, which is esophageal, gastric and the GE junction tumor types; lung cancer; head and neck cancer; and bladder cancer, those are going to be the areas that we focus on with SURPASS going forward. And it's really based on the clinical information that we've seen to date. That doesn't mean we won't treat any other tumor types. The study does allow other tumor types to be treated. And if we see that there are tumor types that really have adequate evidence of expression of MAGE-A4, we're certainly open to exploring that. But really, the focus of the study will be on those tumor types. With respect to synovial sarcoma, we're really focusing on the Phase II SPEARHEAD-1 study that's registration directed.

Got it. And you are also doing a radiation substudy as well in multiple tumors. Could you talk a little bit about rationale there? And what prompted you to actually look at this combination?

Sure. So we -- there's evidence both in animal models and anecdotal evidence in patients from other systems that low-dose radiation can change the immune impact of tumors. So that could include -- hypothetically, that could include trafficking or antigen presentation in the tumor. So we decided to evaluate whether the combination of low-dose radiation and our MAGE-A4 T-cell could impact cancer in patients with cancers. So this is a trial that's open to a variety of tumors that express MAGE-A4. The first patient who was treated had melanoma and had a response as we previously reported. So this trial continues to be open and is still enrolling.

Got it. That makes sense, actually. I have a couple of investor questions, if I may ask them. So one question is, in your trials, do you see tumor infiltration? And is there a biomarker assay that can be run to make sure that these cells do reach the tumors. Is there anything like that?

Yes. This is one of the questions that we're most interested in, not only how can we evaluate that aspect, but does it have an impact? And I'll just mention, previously, you said that a dose of 5 billion cells could be a scary number. And that is quite a bit higher than CAR-T cells in hematological tumors. So we're interested in whether the increase that we've seen and the need for a larger numbers because of the tumor localization. This is an area of intense interest. Adaptimmune has not yet reported extensively on our results there, but we continue to pursue this question.

Got it. And could that -- could -- like once you get the answer to this question, could it be a means to find the right cohort of patients as well? Because there could be some patients who are more responding -- who are better responding versus others and based on biomarkers, do you think that question could be answered?

That would be a holy grail. Can you find the patients that are capable of responding? And certainly, that's a hypothesis that we are investigating. We have a very active translational group. We rapidly turn our translational data back into clinical applications. We haven't reported on any of this, but Adaptimmune will report results for whatever we're investigating and when we get meaningful results, we'll report them at scientific congresses.

Great. I mean, I'm getting quite a few questions from the investors. So another question is, can you please speak to the relevance of HLA partially matched approach? Would your therapy work for tumors that lose HLA or MSC expression, which you commonly see with solid tumors?

Can you repeat the question, my video got paused.

Sure. Can you speak to the relevance of the HLA partially matched approach? Would your therapy work for tumors that lose HLA or MSC expression that you commonly see with solid tumors?

Antigen loss, either through loss of expression or loss of HLA, is an ongoing question that we're investigating. But we haven't reported any results from our MAGE-A4 study. What I can tell you is that we're not only looking at HLA but all of the antigen presentation machinery as well as the antigen expression. So in terms of partially matching HLA, the one approach that Adaptimmune has in the pipeline we refer to as a HIT, or HLA independent T-cell receptor. And we're quite excited about the ability to move this into clinical investigation. In this case, antigens expressed on the surface would be recognized and engaged by a T-cell receptor in a non-HLA specific approach. And so in the future, we have the opportunity to investigate those receptors, those HITs, and we have the opportunity to put them into an allogeneic platform, which can be engineered to be off-the-shelf and not patient specific.

Got it. One another question we are getting is that, when should we expect an update from the gen 1 basket trial or gen 2 SURPASS trial?

So I can address that. With respect to the gen 1 basket trial, that study has completed enrollment. And we provided an update at ASCO on the vast majority of the data. We will provide an update on the sarcoma data with respect to duration of response and translational information, as we're able, later this year. We're also planning to provide an update as it relates to the second-generation Phase I trial SURPASS later this year as well. We're unable to sort of give specifics about conferences based on embargoes, and abstracts are not necessarily accepted at this juncture. But we do intend to sort of deliver information at conferences and really try and move away from sort of patient-by-patient presentation of information and focus on sets of data that can be more meaningful and predictive. I also think that it's important to just sort of set expectations here a little bit. Like all the other people conducting cancer research trials, we've had to manage through the COVID-19 pandemic. And I think we've done a good job at that, and have been able to continue to treat patients and recruit patients not as robustly as likely would have been the case in the absence of the pandemic, but still being able to do it when safe and appropriate. But it does limit the quantity of new patients that we might be able to provide updates on. What we will say is that we'll provide an update on at least the patients that were presented in our May, June time line presentation of data as well as any new patients for which we have meaningful data in those programs later in the year. So I hope that answers the question.

So basically, you'll have some update from the SURPASS as well later this year at a medical conference. Is that fair?

That is our intention.

Got it. Very helpful. I'm getting quite a few questions. I have never seen so many people asking questions. So it seems like it is very popular right now. One more question. Do you -- so it's not just Adaptimmune, generally, for these conferences, I don't get questions from investors, but this time, it is a lot. Do you plan to redose patients? And if -- is it a possibility with the TCR therapeutics? And if that is the case, how do you plan that? So redosing...

So our studies do -- our Phase I studies do generally provide for the capability for redosing, and we're certainly exploring that in the right patients. So when I say the right patient, I mean that at the time of progression, their tumor still expresses the target. And they remain fit enough to have a second infusion. The data to date has been mixed. We've seen responses in patients that have had second infusions, but it's certainly not something that gets done in every patient. We're really -- I think we're really focused more as compared to second infusions on development of more potent second-generation products, combinations. And I include in that the addition of low-dose radiation, and I think that our focus is really on next-generation programs. And I'll also add the allogeneic program to that, where an off-the-shelf product that can shorten the time that patients need to wait and provide for greater consistency in the product from patient to patient that doesn't have each patient having to provide their own cell material is a direction that we would that we really plan to travel in the future. So that...

Got it. Sorry, I mean, this is very helpful. Maybe one question I wanted to touch upon, you have recently showed the updated data from AFP at the Liver Congress. Could you touch a little bit upon that data, what you have learned so far? Of course, you have seen the first response sometime back. But now you have, I think, 5 patient data total. So what you have learned from that data set? And what is the direction you're taking with the AFP program? Because I think you discussed that you could actually expand into other indications as well over the next year.

Yes. So there are sort of 2 parts to the question. First, with respect to the data to date. I mean, we presented 4 patients data at target cell dose that is our group III and expansion cohort patients at the International Liver Congress. And it is the first patient that had the complete response, which is really encouraging. Complete responses are not often seen in liver cancer trials in late-stage patients. So we feel that there's clearly the potential for efficacy with this program. We really feel the other patients that in group III did not show response, and then the next patient in the expansion cohort had stable disease at their first assessment. So while the first patient was very encouraging, there's clearly room to understand why some patients are responding, other patients may not be. That's where the translational work will come to play. And we also just really need to treat more patients with this target cell dose of 5 billion to 10 billion cells to see what the true response rate is with this program. As any responsible drug company should be doing, we're looking at ways to potentially enhance that either through patient selection or understanding of the right patient population, second-generation approaches, combination approaches. All those things are -- we may pursue, depending on how the next several patients play out in the first generation Phase I program. So I think that those are our thoughts on -- with respect to the direction of the AFP T-cell receptor. We do believe that there's great promise this very difficult-to-treat tumor with this approach. You mentioned other tumor types. I just want to sort of, again, manage expectations around that. The inclusion of other tumor types was really driven by the investigators in the program saying, "Hey, we've got rare tumor types that express alpha-fetoprotein in patients without significant treatment options. Could we include them or treat them with this T-cell receptor?" So rather than just sort of doing it as a bunch of one-off single patient IND type approaches, we opened a cohort of the study to allow these patients to be treated. And -- but these are rare tumor types. And I think the focus of this program for us is primarily in hepatocellular cancer, but we are very open to trying to meet the needs of these patients with rare tumor types that are very difficult to study and to see whether we can deliver some efficacy to this population, too.

Great. This is very helpful. And maybe one last question for Gavin. So we did see a nice partnership with Astellas earlier in this year. Maybe just wanted to touch upon how important it is to have a big pharma partnership at this stage for you as well as should we expect more such deals? Or do you think you are set on the deal front? And I think it's basically just executing, which is the key here.

Yes. I mean, we were really pleased to enter into the agreement with Astellas. It was important at this stage where the company was, and we've gone to the ED department and team, and we continue to look at potential partnerships across the board. So yes, we're actively looking across there.

And I mean, going forward, in terms of some kind of commercial partnership, do you think you would need a commercial partner eventually or -- for each of these assets separately? Do you think this is something you can do on your own?

Yes. So at the moment, the intention is, as we touched on, already has been a fully integrated cell therapy company that includes having our own route to market and certainly, we're working hard on supremacy to do that. And never say never, but at the moment, we're backing ourselves to develop that capability in-house.

Great. Very helpful. Thank you, Gavin. Thank you, Elliot. Thank you, John and Mark. Really appreciate you giving us time here. I know we are coming. So thank you very much and all the best for the rest of the year, and hope you have great meetings today. Thank you.

Appreciate your time, Mohit, and for everyone joining the call. Thank you.

Thanks so much.

Thank you, everyone.