Adaptimmune Therapeutics plc (ADAPY) Earnings Call Transcript & Summary

Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. Before we start, please note that this webcast is for Morgan Stanley's clients and appropriate Morgan Stanley employees only. This webcast is not for members of the press. If you are a member of the press, please disconnect and reach out separately. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have from Adaptimmune, CEO, Adrian Rawcliffe; CFO, Gavin Wood; and CMO, Elliot Norry. Welcome, everyone.

Hi. Great to be here.

So for those who may not be familiar with Adaptimmune, can you provide a brief introduction?

Apologies, little technical difficulty here. Can you hear me?

Yes.

Yes, we can.

Fantastic. So Adaptimmune is a fully integrated cell therapy company with plans to launch our first product in the U.S. in 2022. Our initial differentiator was our proprietary capabilities to engineer T-cell receptors to recognize solid tumors. And this technology led to us reporting in January and in May responses in a broad range of solid tumors with our MAGE-A4 targeting program, including melanoma, head and neck, lung cancer and gastroesophageal cancers. And based on these data, we're starting a Phase II trial in gastroesophageal cancers early next year. We also reported compelling response and durability data with our lead treatment, ADP-A2M4 for synovial sarcoma. Most recently, that was reported at ASCO. And our SPEARHEAD-1 trial, which we intend to use for registration, is enrolling rapidly and subject to all of the usual caveats that will form the basis of our ability to launch the product in 2022. And we reported a complete response in our ADP-A2AFP program, targeting AFP in hepatocellular carcinoma. And these data were recently updated at the International Liver Congress. Finally, beyond our existing portfolio of 3 therapies in various trials, in multiple solid tumor indications, including combination studies, we've built a fully integrated company. And we think that's a really important part of the value proposition of Adaptimmune, is the ability to actually deliver these cell therapies to patients, which requires a unique set of capabilities for cell therapy companies. And these capabilities scale as we develop and launch new therapies. We have a rich pipeline of other cell therapies that are not yet in the clinic and also not really well recognized at the moment. A fairly advanced stem cell-derived allogeneic platform as well that we're developing, including in collaboration with Astellas in a deal we signed in January of this year. So we plan to share more details about all of the early phase pipeline and our existing clinical products at an update in our Investor Day this -- later this year in November.

Great. Well, let's start with your AFP program. As you said, a few weeks ago, the Phase I data were presented at the International Liver Congress, which included a complete response. I guess can you tell us about the study and then the patient population being studied and what you saw?

Elliot?

I certainly can. Thanks so much for the question. So the study directed against alpha-fetoprotein, the T-cell receptor directed against alpha-fetoprotein, was a Phase I study that was initially designed for safety. So a dose escalating study where we initiated with a very low dose of cells and then escalated up to the target dose of cells, which really we just got to that target dose in the latter part of 2019. The safety component was important because alpha-fetoprotein is made by noncancerous liver cells as well, especially in people with underlying liver disease. So we had to establish that the T-cell receptor would recognize tumor, but not recognize the noncancerous liver and attack that. So we were cautious in the early part of the study, but have now gotten to a point where we've seen responses with the target doses and have not seen T-cell-related liver toxicity. So that in itself is very encouraging to us that we could approach a target that was not solely manufactured by tumor, but manufactured and accessed by the tumor as compared to noncancerous tissue. So as I said, we started dosing patients with the target dose approximately end of -- latter part of 2019, and the first patient treated at the 5 billion transduced cell dose had a complete response. That patient had an initial partial response and then by -- latter in their course their tumor continued to shrink to the point of a complete response. And that patient has now progressed at week 32 with a new lesion in their liver, rather than progress -- rather than recurrence of the prior lesions. We've also treated 3 other patients as reported at International Liver Congress with that approximate 5 billion cell dose. And unfortunately, 2 of those patients have not responded, and the other has a best response of stable disease. So we're still in the exploration part of this study. We feel like we need to treat more patients at the 5 billion cell dose to really establish what the response rate is. In the patients that have not responded, we've still seen some evidence of antitumor activity. Alpha-fetoprotein levels have been transiently dropping. And in some patients, some lesions have gotten smaller, even though they don't meet the criteria to call them a response. So we believe that the T-cell receptor is active, and that it does have the potential to treat liver cancer. It's just that we need more translational data and more patient experience to really understand exactly what the response rate is and what future directions ought to be depending on what we see. So that's essentially a summary of the liver cancer program with the alpha-fetoprotein-directed T-cell receptor. The one thing I'll add about the complete responder is that they started with an alpha-fetoprotein level of almost 6,000. Normal range is up to about 10. So a very high level of serum alpha-fetoprotein. And with treatment, their serum alpha-fetoprotein progressively came down from 6,000 to very close to the normal range, just above 10, and stayed there for quite some time. So again, sort of evidence that the T-cell receptor is affecting the target.

And for the patient who had the complete response, like how many prior lines of therapy did they have before starting in the study? And then for this type of patient population, what kind of PFS and duration of response do you see as clinically meaningful?

Yes. So I think that those are good questions. So the patient that we treated had 2 prior lines of systemic therapy. With the complete -- the patient with the complete response had 2 prior lines of systemic therapy, both an anti-angiogenic agent and a checkpoint inhibitor. They had also received prior local regional therapy, which is very standard in liver cancer. Patients get local regional therapy until that's not viable and then they move on to systemic therapy. So he had been previously treated with essentially the 2 types of agents that are standardly used at this point in liver cancer. I do think that the paradigm for prior treatments is changing in this disease. When we started this study 5 years ago, the only approved -- or 4 years ago, the only approved treatment was sorafenib. And at this point, there are multiple approved first and second-line treatments. And it really looks like the field is moving towards combination anti-angiogenic plus PD-1 inhibitor as first-line therapy, or I should say, a checkpoint inhibitor as first-line therapy. So what happens for patients that progress after first-line therapy, I think, is where we're looking to for -- in the current landscape to potentially fit in. And we think that with -- the combination therapy that's likely to evolve to being first-line treatment is associated with a 30% response rate in general -- approximately 30% response rate with a median duration of response of approximately 8 months. So if you use that as sort of a bar for first-line treatment, it's generally our feeling that for second-line treatment, we'd like to see a response rate of around, let's say, similar, 30%, and a duration of response or PFS of at least 6 months. That's sort of our own internal benchmark. But I think that that's also a little bit oversimplified. If the response rate is slightly less than 30%, but the duration of response is really very good or even there are complete responses, or let's hope even a cure, then I think that, that 30% doesn't necessarily represent where we could go with that. One of the reasons we feel we need to treat more patients at this juncture is that we've only treated 4 at the target dose. And 1 has had a very nice response that would certainly meet the criteria that we're talking about with an 8-month PFS and a complete response. So is the response rate 25%? Do we -- is it 40% or 50%? Is it -- do we just treat 1? And if we get up to 10, do we just see 1? And if we get up to 10, there are no more responses? We really need to define that before we can make decisions about how to take this program forward. And we'll gather the translational data along the way to make it work.

Sounds good. And when might we see the next data update? And what would your expectations be with regard to hematologic safety at the higher doses? Like for instance, if you see better efficacy at the higher doses, but also increased hematologic safety signals, is there a way to manage that, given that it's mostly in the first 7 days?

Yes. So first of all, we don't really expect to put data out for the AFP program for the remainder of 2020. But as it relates to hematologic toxicity, we really think that's primarily driven by the lymphodepleting regimen. And we've seen similar tolerability in the liver cancer population from that standpoint as the rest of our programs. We're using the same lymphodepleting regimen at this point. So while there is hematologic toxicity that is primarily in the first week or improves by the first several weeks of treatment, we think that, that is manageable.

Great. Well, let's move on to your MAGE-A4 program. How many patients in the U.S. express MAGE-A4?

So MAGE-A4 is expressed across a broad range of epithelial tumors and others. And it's typically expressed in the sort of anywhere from 15% of the patients up to 40% of the patients in those tumor types. And I think the sarcoma and synovial sarcoma, in particular, is the exception with higher expression rates, probably more like 60-plus percent in synovial sarcoma. Later on this year, probably at our Investor Day, we are going to roll out the results of our broad screening program, which we've been conducting, including the screening that we've done in conjunction with our partner, MD Anderson, to understand the prevalence of MAGE-A4 expression at useful levels across the broad range of solid tumors. And when we do so, I think it will be seen that MAGE-A4 is a very significant cancer target. And actually, we're quite pleased because we feel that we have clinically validated that target, which I think will be a significant contribution to the field. With 1 caveat, the nature of the target itself means that it is really only addressable via mechanisms that recognize the peptide MHC complex, primarily a T-cell receptor. So although I think it's a very significant target, its addressability will be restricted to those companies that can develop TCR-based therapies or functionally equivalent therapies, such as SPEAR T-cells or sort of bispecifics with the TCR.

And you touched upon this in your introduction. I guess, at ASCO, updated data were presented from the Phase I. Can you just remind us what you saw there?

Certainly. So we saw a -- we did an update on the sarcoma patients from the -- and also the non-sarcoma patients, and that was presented by Dr. David Hong. In the 16 patients with synovial sarcoma, for whom we presented data, we showed best overall response data from 15 of those patients. And of those 15, 7 had responses -- had RECIST responses. But actually more interesting because that response rate was very similar to the response rate that we had last year, was the durability of the responses. And the median duration of response was approximately 28 weeks. And in particular, there were 3 patients who were still in response, although they're roughly 1 year -- at the 1-year point. So given the relative paucity of effective therapies in the second-line setting in synovial sarcoma, this obviously represents a very significant opportunity for patients. In the other indications, we presented data from both our first-generation program that showed those results in synovial sarcoma and our second-generation program, which is the SURPASS trial, which uses the same TCR, but uses a CD8 alpha coreceptor designed to improve potency, effectively converting all of the cells we give into killer T-cells. And we reported responses across those 2 programs, which use the same T-cell receptor in lung, gastroesophageal cancer, head and neck and also bladder cancer. Although bladder cancer wasn't a RECIST response, but there was a very substantial reduction in the target lesion, approximately 67% in the target lesion. So very significant antitumor effect. So on the basis of that, we're focusing SURPASS on those indications in order to gain enough patients across the trial, in order to understand the nature of the signal. And we're initiating on the basis of the 2 responses in gastroesophageal, a Phase II study with the second-generation ADP-A2M4CD8 in the early part of next year.

And so you're running SPEARHEAD-1 as a registrational trial. What has the feedback been from the FDA on the strategy and the design of the single arm study? Has there been any pushback?

So the -- with respect to FDA and European regulatory approaches, we've had very favorable discussions with both agencies and have applied for programs that would allow us to have accelerated review as well as the opportunity to discuss with the FDA at regular intervals as we move through the program. Specifically in the United States, we've obtained RMAT designation; and in the European Union, PRIME designation. So both of those include an assessment by the agency that this is a promising therapy. It's not just based on the fact that it's a rare disease. So we're very pleased with that. With respect to specifics of discussions with agencies or the thresholds required for advancing the program, generally, we're not discussing details of that. And as you know, the agencies always leave specifics of -- sort of the threshold for approval to review. So it's -- and that's fair enough.

And can you remind us the endpoints of the SPEARHEAD-1 study? And when do you expect to report data?

So we're planning to report data after we've completed the assessment of the study, which would be approximately 6 months after the last patient is dosed. We're currently enrolling that program in over 20 centers in North America and Europe. And we believe it's on track to complete dosing in the first half of 2021. So add 6 months to that, some time to evaluate the data, and that would be when one could anticipate seeing reportable data from that program.

Can you remind me -- I think, as of May, you had identified over 30 patients with the right HLA and expression of MAGE-A4. How many patients have now been identified? And then, I guess, what kind of response rate and duration of response do you need to see to be clinically meaningful?

Yes. So I can -- we haven't guided on specific enrollment and treatment numbers beyond that previous designation. But we are -- we do feel that we're on track to complete the study as discussed with enrollment completing in the first part of 2021. With -- so I think that that's the answer to the first part of the question. Just remind me, the -- you want to know about the...

The response rate and the duration of response.

Yes, the response rate. So as you may know, we started this study with the intent to enroll 60 subjects, and we reduced it to 45 based on the favorable response and -- that we saw in the pilot study. And that we no longer needed to establish futility. So the study is designed statistically to show a meaningful difference between the current available therapies, which have generally response rates of 5% to 15%, but we chose a threshold of 18% to be on the high side of that. And then the 45 subjects enrolled is designed such that if there's a 40% response rate in the trial, then that would be statistically meaningfully different from what's historically expected from the currently available therapies. That being said, I don't want to say that if -- for example, there's a slightly less than 40% response rate, but the duration is very good, that, that wouldn't be meaningful for patients. But that's the way that we designed the study, to be able to show that kind of difference, essentially 40% response rate being statistically meaningfully different from current therapies, assuming sort of the highest available response rate from those prior therapies.

Great. And you're also running the SPEARHEAD-2 study in combination with pembrolizumab for head and neck. What gives you confidence for this regimen?

So I think that a few things. First of all, we've seen evidence of activity in the MAGE-A4 directed T cell receptors against head and neck cancer. 1 response in the pilot study and 1 response in the SURPASS study. So -- and that's out of 4 patients treated. So we're optimistic about the ability of the T-cell receptor to address this tumor type. In general, we think it makes sense just from a scientific standpoint to add T-cells that are specifically directed at the tumor with an agent that affects the microenvironment, so as to take the brakes off the T-cells. In addition to that, with -- we've shown in some of our patients that giving SPEAR T-cells can be associated with upregulation of PD-1. So taking those things together, we think that this makes sense. Head and neck cancer is a particularly good target for this and that pembrolizumab is first-line treatment for a portion of the population with head and neck cancer. And although it's first-line treatment, the response rate is around 20%, with the duration of response that's measured in months, not years. So while we'll be incorporating the use of the approved first-line treatment, there's still quite a bit of unmet medical need for these patients. And this provides us with the opportunity to look at SPEAR T-cells really in sequence immediately following first-line pembrolizumab than in combination with PD-1 inhibition combined with T-cells. So we think it's very innovative to look at it this way and provides us with a way to look at the combination, both scientifically and also at sort of an earlier sequence of therapy for T-cells.

And maybe in the last few minutes, just 2 hopefully quicker questions. One is that you plan to provide an update on SURPASS data in the fall. So what should we expect to see with the update? Will it be more patients or longer follow-up? And how is this likely to be announced? Is it more of a press release or at a medical meeting?

So we plan on updating on clinical data at scientific congresses. And we haven't been specific about which one in Q4 we will be presenting the SURPASS data in, but we have said it will be in Q4. And so a medical congress in Q4. And that reflects our desire to get away from presenting dribs and drabs of little bits of data through non-peer-reviewed and non-medical congress approaches, which I've been clear about since the beginning of this year. And I think we have an opportunity now to focus on allowing the science to speak for itself at medical congresses albeit approach.

Sure. Maybe 1 last question. So you're planning to hold an Investor Day in late November. What should we expect at that event?

So the first thing people shouldn't expect, based on my previous answer, is an update on clinical data. Yes. So -- but what I do think is that the story of Adaptimmune, which has evolved across the last few years, is actually quite poorly understood by the community. And in particular the requirements and the capabilities that we've built to be able to actually develop and commercialize these therapies as opposed to simply focus on the science behind them, I think, is a really critical piece that we'll be showcasing there. Also I think the focus on our clinical data completely justified and the question of whether you can get cell therapies to address solid tumors, we've now answered that. The answer is you can. So now the question is, well, what else have you got? And so we'll also be showcasing, I think, the breadth of the research that's going on in the company, including our allogeneic platform and the other approaches we have to targeting, including our HLA-independent TCR approach. So it will be an overview of the strategy and the capabilities that we've built as a company.

Great. Looks like we'll have to leave it there. Thanks to you. Thank you all so much for your time.

Thank you so much. Take care.

Thanks. You too.