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

Excellent. Good afternoon, everyone, and welcome to the second day of the JMP Securities Life Sciences Conference. My name is Ren Benjamin, Senior Biotechnology Analyst here. And it's my pleasure to introduce Iovance, in our view, the leader in TIL therapies for solid tumors and a company that's on the cusp of submitting multiple BLAs. Here to tell us more about the company is Igor Bilinsky, COO; and Sara Pellegrino, VP of IR. Welcome, guys, nice to see you. We never really know exactly who's in the audience, whether they know of the Iovance story or not. And so Sara, maybe I'll hand it off to you to give us a quick synopsis of the Iovance story as a whole.

Sure, and thanks so much, Reni, for hosting us today. So Iovance is a late-stage oncology company. We're developing novel cell therapies initially focused on addressing solid tumors for patient populations with significant unmet need. Our pipeline is based on tumor-infiltrating lymphocytes, or TIL, technology. And the TIL technology is designed to enable a patient to fight their cancer with their own cells. So TIL are immune cells naturally found in the body. They're regularly attacking cancer cells in all of us who are healthy. But when a person gets cancer, the disease prevails over the TIL cells, and the TIL are not able to do their normal job. The basis of the TIL therapy started with Dr. Steve Rosenberg at National Cancer Institute, or NCI. And the concept is rather simple, and that is to take a sample of the tumor so that you can expand and rejuvenate the TIL outside of the body and then deliver it back into the patient in much higher quantity so that those cells can fight the cancer. The process for growing TIL has been quite complex over many years, particularly if you think about the manufacturing, which had traditionally taken several weeks or months. So Iovance over the past several years has learned a lot about TIL development and manufacturing. And today, we have proprietary TIL processes and production, which are centralized, scalable and protected by a strong intellectual property. To date, across all of our clinical studies in various indications, we've treated more than 450 patients. And we have a success rate in manufacturing north of 90%. And in terms of the patient and the manufacturing, the process really begins when, first, a surgeon resects a tumor sample and sends it to a centralized manufacturing facility. Right now, that's our COO. In the future, we intend that to be our Iovance Cell Therapy Center. And there, we can grow and enrich the TIL cells in the tumor to at least 1 billion cells. And this happens during our 22-day Generation 2 manufacturing process, and this is a process that allows the TIL cells to flourish. After we've grown the TIL and the cells meet our prespecified release criteria, we then cryopreserve the cells and we send them back to the treatment center. And at that point, the TIL is ready when the patient is ready. So when the patient comes in to receive the treatment regimen before we infuse the TIL cells, they undergo a lymphodepletion regimen. And that is to knock down the hostile microenvironment of the tumor to get the body ready to receive the TIL. After that, we infuse the TIL back to the patient. And after the TIL is infused, it's followed by a short course dose of IL-2. And the purpose there of the IL-2 is to help the TIL expand in the body, not intended to be therapeutic. To date, in the 400 -- among the 450 patients treated, we have clinical data for TIL in several indications. For our lead program, lifileucel and metastatic melanoma, we've seen deep and durable responses following onetime administration in a cohort of 66 melanoma patients who have progressed in their disease following anti-PD-1 therapy. More specifically, our latest update at ASCO, which we will highlight further, median duration of response in these patients has not yet been reached at 33 months of median study follow-up. Our second pivotal program is in cervical cancer, and we have also seen compelling clinical data there in patients following progression after chemotherapy. This is our second pivotal program. And we also have a registration supporting study ongoing now in non-small cell lung cancer. And we're also -- in addition to the TIL monotherapy studies, we are increasingly excited about moving TIL into earlier lines of therapy in combination with other treatments, including pembrolizumab. So over the next 5 years, we really hope to be a successful, fully integrated cell therapy company in solid tumors and to be the leader in TIL development, manufacturing and commercialization. Our longer-term development strategy is to broaden the use of TIL in new indications and earlier treatment settings for more and more patients. For example, we are investigating next-generation approaches to use selective TIL to be more specific to the tumor and also genetically modified TIL using the TALEN technology that we licensed from Cellectis. That's designed to be more resistant to evasion mechanisms used by cancer. In addition, we have a novel IL-2 analog and a third-generation manufacturing process, which is called Gen 3. That is a 16-day process that's now in the clinic and a few of the cohorts within our various clinical studies. So we've moving these early programs forward, and we're excited, and we'll allow more updates as things progress.

Terrific. Thank you very much for that overview. And look, before we dive into the specifics of the ASCO data, you had a very nice ASCO update, which is usually how I like to start these conversations. I think a good part of the audience and probably a lot of your one-on-one meetings would like to learn more about potency assays, where you are with the potency assays. And then I always get this third question from investors, what does it have to do with -- oh, yes, potency assays. And I guess I'd like to start off the talk, obviously, focused in on that, right? The potency assays you've done to date and how we're incorporating them into maybe the ongoing registrational studies. But maybe just to start off, I think there's some considerable confusion in the marketplace regarding what iteration of a potency assay the team is currently working on, right? I thought originally that there was a first gen sort of established potency assay that you'd gone to the agency with, that you had proposed some second gen potency assays, and now that you might be working on a third gen potency assay, which is likely what you're going to go to the agency with in the second half. I could have that all backwards. So I'd love for you to just maybe straighten it out for us.

Yes. So potency assays are certainly the hot topic these days, and we have today with us Dr. Igor Bilinsky. He is Chief Operating Officer of Iovance, and he is a subject matter expert who can elaborate this work that we are doing with the potency assays to address the FDA feedback. Igor has more than 20 years of industry experience, including management, consulting and C-suite roles at biotech companies, and he currently oversees our operations at Iovance, including internal and external manufacturing. So Igor, do you want to dive into the questions?

Thank you, Sara, and hello, Ren. To begin with, we are confident in our suite of assays, and we think we have a good understanding of what FDA wants based on the feedback that we received. So to recap the history, we submitted data in the first quarter to address FDA questions for our first assay, which is considered the gold standard assay, which is well established, as well as the recently validated second assay. In May, FDA provided us with a lot of feedback regarding these 2 assays, and we've learned a lot from these FDA interactions. In parallel over the last approximately 9 months, we've worked on developing a new set of assays to show activation of T cells and/or their ability to kill tumors. So regarding the potency assay used in our registrational studies, we're confident in both our clinical data and the product release criteria used to conduct these studies. To be clear, the FDA has not raised an issue around efficacy or clinical data. And as you know, we've already reached agreement with the FDA around the amount of clinical follow-up for melanoma and BLA. And the purpose of potency testing is to discriminate between potent and subpotent lots of autologous products, for example, to detect manufacturing failures. And as you know, the requirements for commercial release assay is generally stricter than for clinical release assays. So the FDA has raised some additional questions around how we distinguish between potent versus subpotent product batches in the manufacturing process for commercial release, and that is what we're working to address now. And we are quite far along that path, again, using this suite of first gold standard assay, second assay, and then the third set of assays that we've had in development for the past 9 months.

Okay. So just to probe a little bit further. I was under the assumption that maybe the first assay and the second assay, that the FDA kind of got back to you and said, "Look, these won't do. We need something totally new." Did I hear you right that, actually, it might be a combination of like the first, second and the third, and that combination of assays might actually fulfill the FDA requirement? Is that fair?

Ren, thanks for bringing it up, and thanks for an opportunity to clarify that. So we have not said that the FDA is not keen on the initial assays. But what we've said, they continue to have questions that we believe we can address by doing additional assay work. And as I mentioned, we submitted data package for the 2 assays earlier, received feedback. And then a new set of assays is available. So we're looking at this whole array of assays. And where we will come out exactly, that's still to be determined. It may end up being 1 assay, it may end up being a matrix of 2 assays. That's still TBD, but we have basically a range of these approaches that are at our disposal right now.

Got it. And when you go to talk with the FDA with these new assays, we've been asked this as well, is it kind of like 1 assay? Is it 2 new -- forget the gold standard and the second assay that you submitted already, right? So we're talking about the third batch, if you will. Is it a group of assays? Or is it just 1? And kind of related to this, the reason why I ask is we assume, and I'd love to be corrected if I'm wrong, that you have to keep going back to the samples from the clinical studies, right, to validate these assays or to sit back and confirm that these assays actually work. And I would think that by the time you go back to the FDA, I don't know, if you're going with additional assays as opposed to just 1 and seeing what the FDA thinks. About how many assays will you be going to the FDA with new novel assays?

So it's basically 1 assay can be also matrixed within the assay because just to step back, when you're discussing an assay, there are different ways to stimulate T cells, and there are different outputs you can measure. You can measure cytokines, you can measure cell-killing ability. So all of that could be achieved with 1 assay or with more than 1 assay. So all of that is potentially on the table, and we're looking at various approaches and look to present that to the FDA in the second half of this year. We're confident that, that time line is a good target based on where we are, how far advanced we are in development and how well we understand the feedback that the FDA has given us and then move that forward to a BLA submission in the first half of 2022. The second part of your question is very important. So there -- when we're working to patent some potency assay, there are 2 aspects of that. First, an assay or an assay matrix needs to be agreed. And after that, release specifications can be proposed and agreed. So our plan upon reaching agreement with the FDA on the nature of the assay or assays is to go back to our frozen samples from the clinical studies to complete the validation work on the acceptable assay or assays. And right now, for our assay work, we're using a mix of research samples and tumor samples we can purchase for testing as well with some clinical samples. We've been very judicious in our use of samples from clinical trials and particularly from pivotal cohorts until we have buy-in from the FDA on the proposed approach so that we will have enough of our patient samples remaining for retesting with the new assay or assays. And again, to be clear, our plan is not to rerun another clinical study, and that has not been part of the FDA feedback or discussions. Of course, FDA can always ask for more information at any time. But based on where we are today, based on the feedback we received, based on where we are in the development, we -- I'll reiterate, we believe it's a realistic plan to hold the meeting with the FDA in the second half of this year and then to follow in the first half of next year.

Got it. Okay. I appreciate that very thorough answer. We had actually -- I was debating this with somebody once, and it's probably very simplistic so don't laugh too hard. We were thinking, what if you could just run a personalized assay, something where, I don't know, you take the -- you're taking a tumor anyway, right, to make the TILs, but you save a portion of that tumor tissue, and you combine it with the end product, your TIL, and kind of show the tumor-killing ability in a very personalized way. It probably doesn't work for a lot of reasons. I can think of maybe one, just like manufacturing-wise, like to have something like that might extend the time considerably. But is that -- are we getting to that kind of level of potential sophistication as we try to develop assays that show these TILs actually work?

Ren, that's an interesting idea. But this sort of assay is extremely difficult in practice, and FDA is not requiring it and has not asked for it. And the main reasons -- some of the reasons you can think of, you mentioned patient tumors are heterogeneous. You'd have to laboriously grow cancer cells out of them, and then cancer cells are notoriously heterogeneous themselves. Thus, they can be metabolically unfit. And there's no guarantee that you're even growing relevant cells and the way to assess them, and there's no way to test them and create a GMP-grade cell bank in time for release. And finally, we know and literature supports that such assays are highly irreproducible. So we believe that would not be the way to go for a commercial potency assay. And again, the FDA has not asked for it and is not requiring it.

Perfect. One final question regarding some specifics about the assay. Back in the 2000s, cancer vaccine companies, especially those that were using autologous cells, right, went through something very similar. They had to go through this whole education process with the FDA and had to come up with a potency assay. And off the cuff, I remember companies like Cell Genesys and Antigenics, which is now Agenus, getting those approvals. I would have thought that the FDA by now, given the CAR-T approvals and everything else, they would be very comfortable with polyclonal, autologous-based cell therapies and that they're kind of like all the questions, they'd just be very comfortable about it. What are the challenges, if you could, this time around that seems to be different than what it was before?

Right. So Ren, the challenges of -- for TIL are similar to those of any first-in-class therapy because we are -- at Iovance, are trailblazing this approach. The complexities of a polyclonal product, I mean, we're pioneering a new path that's unique to TIL and is different from CAR-T. And our hope is that resolving with the FDA the potency assay approach will pave the way for our other TIL programs across indications and potentially be beneficial for the broader TIL overall. That would be a huge win for us at Iovance, for the industry and, most importantly, for patients with cancer who need these therapies. And the bigger picture, we are at the forefront of TIL immunotherapy development, manufacturing and developing next-generation TIL technologies. We've built a very strong and deep portfolio, and we believe we are several years ahead of anyone else. As Sara mentioned earlier, we have provided our TIL products to over 450 patients in clinical trials with an over 90% manufacturing success rate. In our research efforts, we're pioneering next-generation approaches for the TIL program, including faster Gen 3 manufacturing process, TIL -- selected TILs, genetically modified TILs. And we'll have more to say about these programs as they mature. So we are very much at the forefront of this field, including potency assay but also other areas, and are committed to pushing it forward.

Got it. Sort of switching gears a little bit. You have an interim CEO in place right now. Do you think -- and I assume that things are progressing quite well as you're looking to hiring a new CEO. But do you think a new CEO only comes on board kind of after an agreement with the FDA regarding the potency assay and a path forward? Or do you think it could happen even before that?

So we think Iovance is an attractive opportunity and a unique opportunity at this time. And the CEO search is a top priority, and the search has already begun, obviously. The Board is committed to finding a star leader in cell and gene therapy and immunotherapy development and commercialization as quickly as we can. But it's not an overnight process. It typically takes about 6 months, hopefully will be sooner. And while the CEO typically gets very involved with the FDA at this stage of the process, we have a fully competent team at Iovance, including senior regulatory, clinical development and manufacturing colleagues who joined us from leading commercial cell therapy and cancer immunotherapy companies. And this team is committed, dedicated to driving TIL therapy towards the finish line. So we're definitely not stopping until the CEO search is done.

Got it. I do appreciate very much the clarity on the potency assays, the fact that it's -- you're kind of like building upon previous ones, not that like you're scrapping a previous one. That's something that I was not aware of. So let's switch gears real quick for -- again, to remind people of the ASCO data, you had both monotherapy and combination data, first time where we're seeing combination data from the TIL platform, and it's exceeded our expectations and, I think, the markets as well. I'd love to just get your kind of key highlights that you'd like investors to walk away with.

Thanks, Ren. So we were very excited about the data at ASCO. And by the way, for those who did not have a chance to listen to our ASCO updates with KOL, Dr. Hamid, I encourage you to tune in, and the link is on our website. So we presented 2 exciting data updates at ASCO. The first is from our study of lifileucel in combination with pembrolizumab in patients with checkpoint inhibitor-naive advanced melanoma, and the second is an update on Cohort 2 data for lifileucel in patients with post anti-PD-1 melanoma. And that's the one, Ren. You have -- the second one is you have on the screen. So that update is from -- it's another update from the Cohort 2 of the study, and 66 patients were recruited in that cohort, and the primary end point was efficacy for investigator-initiated -- assessed ORR, overall response rate. And secondary end point is safety and additional parameters of efficacy. And we've provided data updates for these patients in previous medical meetings. To remind you, these patients are heavily pretreated and have progressed on multiple prior therapies. All of them, 100%, have progressed on prior anti-PD-1 or anti-PD-L1 checkpoint inhibitors before participating in this study. And 80% of these patients also have previously received anti-CTLA-4 and progressed. So the overall response rate was 36%. Disease control rate, 80%. And an important update compared to the previous data cut at ASCO last year is the median duration of response still has not been reached at a median follow-up of 33 months now. And another encouraging update from the previous data cut a year ago is that responses in many of the patients, more specifically 11 patients, further deepened over the past year. And one of these patients actually converted from partial to complete response at 24 months post lifileucel infusion. So we're very pleased to see the continued durability of response following this onetime treatment with lifileucel in this difficult-to-treat, heavily pretreated patients with metastatic melanoma, and that's especially encouraging if we consider the available care for these patients is generally chemotherapy with a published response rate in the range of 4% to 10% and expected overall survival of about 7, 8 months. So very pleased with this update. And then the second update was from a combination study of lifileucel and pembrolizumab. And these are data in 7 patients with also advanced and resectable and metastatic melanoma or naive to checkpoint inhibitor therapy. And this is from Cohort 1A from our COM-202 study or basket study, which is investigating TIL therapy in multiple settings and indications. So these patients received lifileucel in combination with pembrolizumab, and data were reported for the initial 7 patients in this cohort. And these patients, even though they were PD-1 naive, did have high disease burden at baseline. The ORR was 86% or 6 out of 7 patients responded, including 43% of patients who achieved the complete response, that included 2 complete responses and 1 unconfirmed complete response just because of the timing. The median follow-up was 8 months. While these are early results, we believe that the response rate is impressive compared to available simulation to combination options. And these data suggest that in such patients with checkpoint-naive advanced melanoma, our lifileucel TIL therapy can be safely combined with pembrolizumab and also suggest a potential additive effect. These encouraging data confirm the general feasibility and activity of combination of lifileucel with anti-PD-1 checkpoint inhibitor in early line treatment of patients, and this cohort continues enrollment. And also to remind you, these initial data, they also build upon the clinical data from Cohort 2A in the same basket trial that we presented last year, and that Cohort 2A is investigating TIL in combination with pembrolizumab in patients with head and neck cancer who are naive to checkpoint inhibitors. And the data were presented at SITC last year in November. We reported initial results for 9 patients in that study, and the ORR was 44%, including 11% CR and 33% PR, with a median follow-up of 8.2 months. Following the release of the data in November, we actually expanded the head and neck cohort from the initial 12 to 19 patients and are looking for additional venues for presenting the next data updates there. So ASCO was very busy for us, and we're very pleased with both updates.

That's a perfect segue sort of in the last minute. These are the upcoming milestones that I have, and you can see that it's kind of absent a data update. And so you bring up a good point in terms of the head and neck study, you're enrolling more patients. I'd love to just, maybe in the last 30 seconds, a, outside of this, which I think everyone knows, is there any sort of data update we can expect in the second half of this year, whether from the head and neck study or one of the other studies?

So we -- Sara, I think you're on mute.

Sara, you're on mute.

Sure. So our top priority is to work for the BLA submission. But in light of the recent BLA shift, we're also considering when to read our pivotal data for both melanoma and cervical. We don't have guidance to provide yet, but we are considering that. So stay tuned. And while we're not providing specific data time lines, we're excited about the potential for TIL across several of our programs. In lung cancer, we have 2 cohorts in the basket study, and we look forward to dosing patients in our registration-supporting study in second-line non-small cell lung cancer, which is the IOV-LUN-202 study. And further updates for TIL in combination with pembrolizumab in head and neck and cervical cancer are also underway. And our ongoing early-stage programs in -- that are preclinical, we are also very excited about.

So Sara -- sorry, Sara, just we could get an update this -- in the second half of this year regarding head and neck or not really too sure?

No. We're not committing to data time lines at this point, but these are programs that we are excited about and the treatment settings that we are currently looking at. But we're not giving any guidance.

Got it. Excellent. Well, thank you very much. I know I ran over, but this will be -- this was a great Q&A. I appreciate your time, and look forward to seeing the progress.

Thanks.

Thank you, Ren.

Thank you.

Take care.