Iovance Biotherapeutics, Inc. (IOVA) Earnings Call Transcript & Summary

Great. Good afternoon or good morning, anywhere you are. Welcome to Barclays Global Healthcare Conference. My name is Peter Lawson. I'm one of the biotech equity analysts at Barclays. I just want to thank everyone for taking time out of their day today to listen to Iovance. And if you have questions for institutional investors, please e-mail me to [email protected], or you can ping me on Bloomberg. It gives me great pleasure to introduce Iovance. We've got Maria Fardis, CEO. And just as a kind of introductory question, if you could maybe just talk through the differentiation and kind of the core competencies of Iovance in the oncology T cell space. Thank you.

Certainly. Thank you, Peter, for the invitation. Good afternoon, good morning to you. So Iovance is developing a tumor infiltrating lymphocyte for treatment of solid tumors. These are cells that normally would come to the site of tumor when a cancer cell is detected in the body. In a healthy individual, they normally would clear the potential cancer cells and the disease never prevails. In cases where there may be a genetic predisposition or an environmental factor, the disease may ultimately continue expanding and the tumor sort of evolves and cancer develops. However, these cells, which we call them tumor infiltrating lymphocytes, they'll recognize the tumor when they came to the site of tumor. And typically, the reason they are not able to fight the disease is the burden of mutations may be very high or the tumor microenvironment is very strong. So the concept around Iovance's TIL technology is taking these TILs, getting them out of the tumor, expanding them outside of human body, called ex vivo, into billions of cells. We rejuvenate the cells and we put them back into the patient, and that this is a onetime treatment. Before we treat the patients, we give -- before we give them TIL, we lymphodeplete the patient. So we administer non-MyLab lymphodepletion to remove that hospital microenvironment. We administer TIL, and then we follow that with up to 6 TILs in the IL-2 to make sure that the TILs survive it from the freight. So in terms of core competence is, Peter, you were asking about, the difference between Iovance and some of the other cell therapies is we are developing cell therapies for solid tumor. We are not genetically currently modifying these cells. So these are the patients' own cells. They're autologous non-genetically modified products that are rejuvenated and sort of expanded. And in that sense, there's not a lot of solid tumor companies that are looking after trying to treat the patient with cell therapies. This is a bit more late coming in comparison to CAR T therapy in hematologic malignancies. Those are the differences. The safety profile also is differentiated in terms of core competency. The safety profile is differentiated, given that there is no genetic modification compared to CAR T therapy. Peter, you're muted.

The IL-2 that you have to give, does that in any way kind of preclude the patients you can give it to, the subgroups of patients that may not be able to take therapy?

We, of course, leave the patient selection to investigators. This is something they decide what is the suitable patient. They want to make sure there's adequate organ function. This is on the clinical setting. It is something that the investigators need to make sure the patient is able to tolerate therapy. It is a cell therapy after all. I do want to highlight that this is up to 6 doses of IL-2. So if they feel that the patient is not able to tolerate the 6 doses, they certainly can dose reduce and reduce the number of administrations, and we do see that. Although we have reported in our melanoma setting as well as our cervical data, the 27 patients that we read, that as a median, most patients had received around 6 doses of IL-2. So most patients were able to tolerate the 6 doses of -- these patients that were selected for our studies.

Patients that don't get the 6 doses or get 4 doses, is there any kind of dose relationship with response?

As of now, we haven't seen a very clear dose response. And in fact, the reason we developed this 6 doses regimen came based on Dr. Rosenberg's data. When I had started at the company, the general TIL technology was using IL-2 back in the days based on IL-2 label, which is a fairly complex dosing regimen, but it basically allows per cycle up to around 28 administrations. Now most patients wouldn't tolerate the 28 administrations. Most of them would tolerate around 20 or so as an average dose. And so, that is where the TIL technology initially started with therapeutic IL-2. When we looked at Dr. Rosenberg's data, we noticed that there was not a specific dose response in his totality of his experience with TIL. However, the minimum number that he had administered was around 6. So that's how we selected 6 based on looking at his data. We don't see a specific dose response, but we have checked with many investigators, and they feel that if the patient is able to tolerate IL-2, it is a good idea to allow for TILs that have been growing in IL-2 outside of human body to continue receiving IL-2 because they allows for proliferation survival of the T cells that have newly been infused into human body. So yes, not exactly, there's not a very clear dose response that we see as of now.

Does it in any way preclude you from older patients or frailer patients? I don't know which way you want to think about that.

Given that there's lymphodepletion involved and it is a cell therapy, we generally monitor the patients if they're over 65 very closely. But I don't know if we have necessarily completely decided that in a commercial study, they're going to exclude a certain age group just purely by age group. I think it really has to do with general health and organ function. So I don't know if necessarily an age differentiator can be used more than what is the health of -- general health of the patient.

Got you. Thank you. I wonder if you could talk about, I guess, currency assay, the FDA kind of feedback and kind of where we -- where you stand with that, and we can talk through like the ways forward. Thank you.

Absolutely. So just maybe to summarize for people who may not have been following the story, the products that Iovance manufacturer is released under a matrix of assays. The assays include potency as one of the measurables, but also identity, total viable count, viability and [indiscernible]. And under each of these, there may be more than one assay involved. Our dialogue with the agency started a few years ago when we started the potency discussion. Just kind of fast forward things, in 2020, we were having a discussion with the agency with our potency assay, is sufficiently well-defined as the agency understands how we define our TIL product. And the agency had additional questions that they issued to us in early October meeting. And so that -- we continued answering those questions. In fact, we provided some of the answers already as part of our actions that we had from that site team meeting. We have additional assays that we are developing and validating, and that's the next action for the company to provide additional data on validation of these additional potency assays. We have looked at a number of assays, and we continue developing them in anticipation of having a number of options should the agency would like to see additional assays. We also worked very well with our KOLs and our advisers who are very familiar with TIL to make sure that they understand what is the best potency assay that could define these products. I recognize that these are complex products. This is a little bit differentiated than, say, CAR T products. Not only the product itself is polyclonal in nature, it's highly polyclonal. And we have published that the product can have thousands of clonotypes in there, but also targeting multiple clones. And so that is a unique challenge to TIL, and this is a differentiator why it's able to work in solid tumor versus products such as CAR T that typically target one specific neoantigen. So there are differentiators in terms of TIL being unique as far as what has been provided to the agency before.

And so, the current assays and results you've shown that they're not sufficient at the moment, or its still back in debate?

I think we continue answering questions. And so we -- there's been questions specifically about, for example, provide your line listing of your product, take a look at your statistical methods. And those are specific questions that we have been answering to the agency. But the nature of the dialogue has been more, at this last round, provide additional information, which we have been doing that.

Got you. And the new assays, are those kind of off-the-shelf new assays or they're completely brand new assays that kind of -- only Iovance has been able to develop?

Yes and yes. So we are developing some new assays, and these are -- some of them have been -- there are -- some are new and some are things that we do as part of our research program to characterize our TIL product. It is important to think about any cell therapy company typically has tens of assays that they use in their research portfolio to characterize their own product. Some of these may be suitable for commercial relief and some are not. For a commercial release product, the assays need to be very robust. They need to be short. They need to have raw materials that are GMP manufactured. Ideally, they don't have a complicated intellectual property, connections to various other sort of sponsors. There's many factors that we consider. They need to be short so that we are able to release the product in a timely manner to the patient. So there's many assays that we think about before we nominate an assay as a commercial release assay. And so they -- we did take a look at a lot of our research assays to decide which ones may be fulfilling those criteria.

Got you. And is the FDA, in any way, kind of talking or questioning the results you've had? It's most -- it sounds like it's purely around that potency assay.

At the moment, the dialogue has been around potency assay and what is required and how much data. And again, the request has been for additional data that we have been providing and we continue to provide.

And they've, of course, seen your response rate data, or have they not kind of got to that part of the file?

That's a good question. So we -- as you might be aware today -- yesterday afternoon, the AACR titles was released, and the abstracts are visible now. So the data that we, for example, have at AACR, we have not provided to the agency. There's not been a venue that we provide updated clinical data to them. So they have seen some clinical data, but not up-to-date clinical data to the degree that, for example, we just -- the titles of AACR has gone public. Now if these -- my understanding is that they do monitor the landscape. So they might have seen it just the same way anybody else might have seen the titles, but we have not provided updated clinical data to the agency for some time now.

Got you. So the last update, I guess, of data to the FDA was beginning of the year, or before that?

We didn't have a clinical venue for exchange of information. So the discussion really has been around provision of information to FDA, which has been CMC information. So it has been some time since we have provided clinical data to the agency.

But they've seen that there's kind of clear responses you're getting in -- go on, terribly sorry.

Yes, of course. And yes, absolutely. And you might remember that as part of a discussion with the agency, back in less than a year ago now, about May of last year, they had requested some information. And we provided the Cohort 2 data as well as Cohort 4 at the time they requested to see what was available. We provided that data publicly back in about May of last year. And so that data certainly was provided to the agency.

Got you. Just the fact that you have to kind of -- it sounds like go off, develop new assays deliver them to the FDA, does that essentially set the bar significantly higher for the next kind of Iovance 2.0 or next TIL company that comes through?

This is probably true for the next TIL company that comes through. And I don't know, I cannot become behalf of FDA. Certainly, is there prerogative and decision-making? Presumably, if this is what it takes to define a TIL product, a TIL product is a TIL product. The products that are targeting polyclonal neoantigen distribution, presumably, would have to use the same type of assays. It's a little hard to tell whether the exact same thing will be used for every single TIL company. I think it really is at the discretion of the agency. And it depends on whether the next company would have the exact same product as ours or are they going to be sort of selecting subtypes of TIL, and that's going to be a different profile. So it's a little hard for me to judge because I don't know what the next company would be before the FDA and whether their product is going to have the same type of profile as ours or it's going to have a different profile.

Got you. Thank you. That really helps. And it is solely around that kind of linking the potency of the cell and response, that's that connection they want to kind of show. And of course, that's a lot more complex or a complex product.

The potency actually doesn't have to be predictive of response, I think that's what you're asking, nor is such an assay in existence for, let's say, PD-1 to other products. So a direct prediction of response is not a requirement, but it should be a clinically relevant assay and ideally based on a mechanism of action of the product. So those are slightly different that one should draw that distinction. If we had an assay that was able to distinguish the product, that would be a beautiful biomarker. I mean, everybody would be striving for something of that nature. We're just not so lucky to be able to find a biomarker that so exquisitely is able to say what is the response in patient and what is not. And I also do sort of highlight that even in an anti-PD-1 landscape, where we have a PD-L1 expression as a potential predictor of market, even with those expressers, we're not seeing 100% response. So we always look for a biomarker that's able to correlate with efficacy, but we are not always successful in finding it.

Got you. Thank you. And then just maybe we could talk a little bit about the melanoma data. And is there any -- do you find there's any subsets of melanoma patients where you're not seeing responses, whether it's line of therapy or markers or PD-1 expression or lack of PD-1 expression -- PD-L1 expression? Just kind of your thoughts there about how we should think about dissecting that data and -- thank you.

As of now -- absolutely, thank you for the question. As of now, we have not seen a very clear marker that is associated with the response or lack thereof. In fact, we have looked and we have published sensitivity analysis with, for example, looking at BRAF mutation, looking at ECOG, looking at LDH levels. General markers that have been associated with potential response or -- and this is not necessarily with the TIL, but a lot of other patient populations and other lines of therapy. Patients that are early in line of treatment are generally better patients to treat, of course. So the later the patient is, the higher their LDH levels are, these are more difficult to treat patients. One of the markers that we did publish on was whether a patient is primary refractory or relapsed refractory. We did publish that patients that are primary refractory, they seem to have a slightly better response than relapsed refractory. So maybe duration of time on prior anti-PD-1 is something to pay attention to. We didn't see a correlation to PD-L1 expression. And in fact, we are seeing responses in patients that have a PD-L1 expression that are low. We saw this in melanoma. We also saw this in Moffitt's TIL study in non-small cell. Ben Creelan's data showed that patients that have a low expression of PD-L1 could equally well be responders to TIL therapy. So that might be something that is actually of interest because low PD-L1 expressers may progress quickly on anti-PD-1, yet they seem to do fine in responding to TIL therapy. So there's not a black or white clear marker. But as we think about where is the potential commercial need, consideration of patients that may be PD-L1 low could be an interesting space just because TIL seems to do equally well in those patients. And we know that those patients may be difficult-to-treat with anti-PD-1. So it's a possibility to think about that patient population. But a direct biomarker that allows us to select one way or the other or exclude patients has not really been identified.

Can you give a sense of, just on timing with filing with the FDA, does melanoma happened kind of in 3Q or 4Q? Do you get any sense of timing of when cervical cancer happens, whether that is -- that has to drift into 2022, just the ideas around time?

We don't have any good ideas, and we really need to hear back from the agency before we are able to give any guidance. One can imagine that they have additional questions, and depending on the nature of the questions, things can be a bit longer. One can imagine that they do not have any further questions, and so we are able to move forward. And those really define sort of the duration of time to the submission. You're also asking about cervical cancer. And that -- just to think about what steps are required in order for us to think about cervical cancer, first and foremost, we really do need to resolve the potency assay issue with the melanoma review team. Melanoma cervical are under 2 different divisions of FDA. So they're not the same review teams. They're 2 different review teams. However, we think that the potency assay has to be resolved with the melanoma review team, the path forward needs to be defined. And then we can engage a cervical review team, and understanding a couple of things from them, how much follow-up they would like to see in cervical, as well as we have talked about potentially Cohort 2 being supportive of maybe registration. It is a discussion that we need to have with FDA to see whether this is something they're interested in or not or are they asking us to do that. So there's -- cervical requires a few more dates. We have to make sure that we address our potency assays with the melanoma review team.

And it would clearly be the same assay for melanoma as it would be for cervical cancer?

We certainly hope so. And right now, that is the nature of the assays we're working on.

Got you. And AACR, I guess it's hard to ask about what we're going to see, but would we get details around potency assay, or is that still not flushed out?

If you get anything that is flushed out, we're certainly happy to share that. Likely typically at the meetings such as AACR, there's 2 components that we usually focus on. There's, of course, clinical updates. We did cut the data for melanoma Cohort 2 for JPMorgan. And we had updated that at 28 months of median study follow-up, we have not reached a median duration of response. But we really didn't show the clinical data around that the swimlanes and waterfalls, whether the data -- the responses are deepening or not. So a lot of that could be shared at AACR. We actually really haven't prepared the slides, so I can't tell you what exactly will be on the slides. A second component of things that we sometimes think about them in terms of what usually goes into an AACR presentation, it traditionally used to be a biomarker early sort of clinical development type of a meeting. And so, if we have some clear statements that we can make around biomarkers, we certainly will be happy to share that information at AACR. So as I noted, we haven't put the slides together. So exactly what would be on the slides is somewhat speculative and subject to additional information, which we might be collecting still.

It sounds like you wouldn't take the -- I guess, the old score AACR approach of biomarkers. It's more so, you probably want to try and get that swimlane, mPFS, HIPAA like of in now as opposed to not.

Yes. So AACR used to be very much a biomarker -- you're correct, very much, a biomarker focused meeting. I think as of late -- it has also now included a lot of clinical updates and sort of innovative approaches to treatment of patients. So a lot of clinical data typically now has been sort of included in AACR. But we will try and see if we can keep a balance between any biomarkers that we might be able to disclose or additional information such as sensitivity analysis and combine that with clinical updates. And again, I am somewhat sort of speculating at this point because we haven't put the slides together. So it's a little hard to tell you exactly what's going to go on the slides.

I fully understand. But it feels sure that position now where at least on the KOLs we talked to that -- and with the data is fantastic and this is hurdled with potency assays. So I guess, most would traditionally think this is the time to kind of start explaining this to a wider audience, right, of this is a therapy that's going to change. So this could be an excellent venue to describe that to doctors.

I totally agree with you. And I think in the past year or so, we're seeing a lot more enthusiasm and inquiries from treating physicians. And so we are really encouraged by the level of engagement that we are seeing from multiple sites that we are engaging as we think about commercial readiness, and that work stream has been ongoing for a few months. And so, that has been really encouraging to see the amount of the enthusiasm that is in the number of different academic institutions. Some have been participating in our clinical trials and some are brand new to this type of therapy.

Okay. Maybe in the last minute, and I apologize for the last minute, but just the strategy for long when we kind of see rollouts of data there?

So I haven't commented to a specific data flow. I've been very transparent that in our Cohort 3A, which is an early-line non-small cell lung cancer patients that are PD-1 naive, it's been a bit challenging to enroll, and we think that there certainly has been some contribution of COVID with patients not wanting to go to academic institutions when they have an alternative therapy that they can receive in their local hospitals. In our Cohort 3B, we do have some patients, and we wanted to make sure we have adequate number of patients and adequate follow-up before we put anything out. We haven't committed to a specific conference or timing just because we wanted to be sure we have enough patients to be able to speak to that. We also have been clear about when we see patients in third, fourth, fifth-line non-small cell lung cancers, many of them really don't have a lot of life expectancy, unfortunately. So we have learned to limit the prior line of therapy for upcoming cohorts and upcoming studies in non-small cell to second-line. These patients are still defined very much with an unmet need in mind, but nonetheless, we are hoping not to see very late-line patients so that they do have the ability to receive the TIL therapy and last enough to sort of yield the data point, and benefit from therapy as well. So we did learn something from that. But in terms of data flow, we haven't committed to a specific timeframe, and nor do I generally commit. I -- we usually submit to a scientific conference and once the abstracts are publicly available, and then [indiscernible] is listed, we announce it.

Okay. Perfect. Thank you so much. I'm going to hand the line back to the operator. It's always a pleasure speaking to you, Maria and...

Thank you, Peter.

Thank you, operator. And thank you, Maria. I hand it back to the Operator.