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

All right. Thank you, everybody. I'm pleased to present Iovance's presentation here at the 41st Annual JPMorgan Healthcare Conference. Before I start, some forward-looking statements I'll be making today, as a disclaimer. Here's Iovance's final numbers and shows our global leadership in innovating and developing tumor infiltrating lymphocyte or TIL therapy for patients with cancer. We've treated more than 500 patients, by far the industry leader with a 90%-plus manufacturing rate, and we have a 22-day industry-leading manufacturing process. We've got 1 BLA submission in progress right now. We've got 6 active clinical trials with 5 different tumor types in the clinic, which are solid tumors. And we've got 5 separate accelerated designations from the USFDA, 3 Fast Track, 1 breakthrough and on RMAT designation. As of the end of the third quarter, we had $367 million in cash. We have more than 60 international and U.S. patents, and we have more than 500 people at the company right now. And then we have a number of partners and collaborators, foremost of which is the NCI and Steven Rosenberg's lab as well as in the Anderson, Moffitt, Yale, Cellectis and many more that we can't really fill in this slide. This is what we accomplished in 2022. We started our first ever rolling BLA submission, which upon approval will be the first ever TIL therapy approved. We presented our critical data, our pivotal data in advanced melanoma, post-anti-PD-1 therapy, at SITC 2022 and in the JITC Journal that accompanies that presentation. We began a Phase III trial in frontline advanced melanoma. We've enrolled additional patients in our LUN-202 and COM-202 trials this year. We've expanded our cervical trial to support registration in what we call Cohort 2. We continued our TIL combination strategy, particularly with pembrolizumab in solid tumor cohorts, many of which you'll see in the next slide. We initiated our first ever and the first ever multicenter genetically modified TIL trial, IOV-GM1-201 of our product called IOV-4001. That's a PD-1 knockout TIL. So it's a TIL where the PD-1 gene has been inactivated. So it effectively combines the power of a checkpoint and a TIL therapy in 1 cell. And then we advanced a lot of new products towards the clinic from our research pipeline. In manufacturing, we executed our commercial readiness activities. We scaled our production at our own facility, we call iCTC. And we executed ATC onboarding, our site onboarding activities and payer engagement as we progress towards a commercial launch this year. This is highlights of our pipeline. Our full pipeline can be found in our corporate deck. It's actually deeper and wider than this. But this is just the highlights of our pipeline. At the very top, we've got lifileucel plus pembro in a frontline study that I just mentioned, began recently. We've also got post-anti-PD-1 TIL therapy. This is our registrational trial that we are filing with the USFDA right now as part of the BLA. We've got lifileucel plus pembro and anti-PD-1 naive patients in our Cohort 1A study, in COM-202. I can talk a little bit about that later. And then we've got our PD-1 inactivated TIL therapy that I mentioned earlier in the IOV-GM1-201 trial. In non-small cell lung, NSCLC, we've got 4 trials running that are shown here in green. And then -- and that's with our LN-145 or unmodified TIL product. And then we've got 2 other trials running with different products. One is the Gen 3 product with a core biopsy. And the other is PD-1 inactivated TIL therapy, the PD-1 knockout TIL that I mentioned earlier. And then finally, in cervical, we've got our registrational study in light blue here at the bottom and our combination study that we reported out at SITC last year. There's a significant market potential in solid tumors. 90% of all cases of cancer are solid tumors. We have 1.7 million cases diagnosed in the U.S. each year. On the right-hand side here, you can see the number of deaths from each indication. Melanoma leads at the top here with more than 7,000 deaths a year in the United States and almost 100,000 new cases. You can see cervical, non-small cell lung and oral cavity, which is for us is head and neck cancer, as well as some other indications here that are of great interest to us. So having a product like a TIL therapy that can work across multiple indications like this has tremendous market potential. TILs have a unique mechanism of action. They're individualized for each patient. We resect the patient's tumor. We expand and rejuvenate tumor-specific T-cells, TILs, that go back and then fight the tumor upon reinfusion into the patient, with lymphodepletion, they can cause a response. And the patient's own immune system will be rejuvenated and amplified by our onetime therapy. And I got to stress, very importantly, our therapies are onetime therapies. The mechanism of action of TIL therapy is unique. It involves TILs traveling from the circulation into the tumor bed, into the tumor microenvironment, where they recognize potential tumor antigens on cancer cells that are presented by the cancer cells and then lyse and kill those cancer cells using a combination of cytokines. Our manufacturing process, like I said, is the industry-leading 22-day manufacturing process, we call it Gen 2. Here's a quick view of the patient treatment paradigm as well as the manufacturing process from patient intake to recovery and discharge. It can take 30 to 35 days in typical cases. The Gen 2 process is about 22 days, as part of that, you can see tumor sample procurement. NMA-LD is nonmyeloablative lymphodepletion, TIL therapy, and then we use a supportive regimen of IL-2 for the patients after they receive their TIL therapy to support T-cell engraftment. Our cell therapy -- Iovance Cell Therapy Center, which is based in Philadelphia, has capacity for thousands of cancer patients. This slide shows the steps as we build the product -- as we build the facility to handle more and more product each year. Right now, we're in Phase I, which is we can do hundreds of patients a year. We are built currently for Phase II though. The only difference between Phase I and Phase II for us is staffing. So we're able to go to Phase II pretty quickly upon additional hiring. And then we have the ability to expand the 5,000 patients a year in Phase III and up to 10,000 patients a year with an additional adjacent site for Phase IV here. Now I'll talk quickly about Iovance TIL therapy in melanoma. There's a tremendous unmet medical need in melanoma. This slide shows the number of deaths, number of cases, the number of deaths worldwide already. I mentioned this in the previous slide. But in the center here, there's bars that show the melanoma drug treated population from actual data. These are the patients right now in the U.S. and Europe that are actually treated right now with drugs. So you can see in the frontline setting, it's almost 10,000 patients a year treated and 8,900 patients in Europe and so on down the lines of therapy. These are our target populations for our frontline therapy in melanoma and our second and third line therapy in melanoma right now. So this is our population that we're looking at today. Available care for these patients in the frontline setting is anti-PD-1 immunotherapy, for example, the 21% to 33% ORR, BRAF/MEK inhibitors. And then the second line is where the real significant unmet medical need exists today, chemotherapy of 4% to 10% ORR and median overall survival of 7 to 8 months is what we have today. This is our Phase II study design. This is the study that we intend to be registrational and have started the rolling BLA on. Cohort 2 and Cohort 4 are the pivotal cohorts of this study. And those are, I'm going to show you the data in a second, but this provides some of the enrollment criteria on this slide. The prior disease -- prior therapy and baseline disease characteristics for these patients show how sick they are. They're extremely ill, median of 3 lines of prior therapy, a range of 2 -- median of 2 lines, range 1 to 7. Almost 74% were retreated prior to therapy showing the recycling of ICI currently in the setting right now. So what's going on right now in the landscape of care is that because there's no option for these patients, the physicians simply put them back on pembrolizumab and drugs like that. 125, which is 82%, received anti-CTLA-4 ipilimumab and 54% received the 2 in combination, so anti-PD-1 anti-CTLA-4 combinations. On the right of the slide here, the disease burden is shown, you can see Cohort 2 and Cohort 4. Cohort 4 patients were even sicker than cohort 2 patients, 84% had greater than 3 lesions, and they had elevated LDH, lactate dehydrogenase, which is a well-known negative prognostic factor for survival with melanoma. Almost 65% of the patients in Cohort 4 had elevated LDH and 41% in Cohort 2. So these were significantly ill patients that we had in our study. Safety was good and well controlled here. We see most of our safety events upfront. We had -- we have a great incidence or a great decrease in the incidence of treatment-emergent adverse events with time within the first 2 weeks, but it was controlled, transient and manageable and supports the benefit of onetime treatment. The ORR in our study is shown on this slide, the efficacy outputs here. Combined it was 31% ORR. Cohort 2 and Cohort 4 together are shown here or shown separately here. One was 34%, 34.8%, and the other was 29%. And you can see that even though the patients were much sicker in Cohort 4, the ORR did not suffer that much. The CR rate, PR rate, SDs and everything else are shown here. And these are all by RECIST. These numbers are from an independent review committee, an IRC read, which is required by the FDA for this type of study. And we manufactured lifileucel within specification in almost 95% of these patients. This slide shows our waterfall plot for the study. You can see that the tremendous benefit to most of the patients on the right-hand side here. It's a very deep waterfall. You've got CRs off to the far right there, and you've got plenty of PRs in between. 79% of patients experienced tumor burden reduction in this study. And again, these are patients who have no other therapy, no other option. This slide shows the duration of response, what we call swimmers plot. You can see here that the responses are durable. They go out very far. The median time from lifileucel infusion to best response was about 1.5 months. They get a response relatively quickly in most cases. And importantly, you can see in the blue box here and as well as on the swimmers plot itself, that responses tend to deepen. Sometimes we have SDs convert to PRs a few months in. Sometimes PRs convert to CRs a few months in. So you'll see blue triangles here that convert later to green triangles as patients' response evens. This duration of response slide shows the Kaplan-Meier curve for our durability. And this slide is important because it shows a flat tail of the immunotherapy curve that you'll expect from immunotherapy like this. The tail is this part which I can't point, but the tail is this part off to the left of the curve here, you can see how it's flat and stable. That's what happens with immunotherapies when they're successful because that basically tells you that patients that are in a long-term response. We've had a lot of discussion this year, this past year about the durability of this data and it's focused on something called the median DOR or median duration of response. In Cohort 4 and Cohort 2, and Cohort 2 was not reached and Cohort 4 was reached at 10.4 months. But what's important really is to look at these datasets with more than one number than median DOR. If you look at the very bottom on the right here, you'll see the DOR as it stood, it's greater than 12 months, the percentage of patients that were still in response, that still were durable at 12 months and at 24 months. And we've broken out Cohort 2 and Cohort 4 here, so you can see them. They're not that different. If you look at the greater than 12 months for Cohort 2 versus Cohort 4, you're looking at 65% versus 44% and at 24 months, 47% versus 36%. So despite the fact that the patients in Cohort 4 were much sicker, durability still was maintained. The FDA has given us positive feedback on this data. Now I'll switch to frontline melanoma. This is melanoma in the frontline setting. I showed earlier on the slide, this is the 9,000 some patients a year in the United States. Right now, we're running a cohort called Cohort 1A in our COM-202 study in this line. We've got a 67% ORR, and we've got durable responses in these patients, and we've got a Fast Track designation from FDA as a result of this. You can see here on the waterfall slide that we've got some deep CRs and we get a very high CR rate. This is data very similar to what Steven Rosenberg generated at NCI with 101 patient dataset, where we saw a 56% ORR rate, and you saw a 24% CR rate. And patients that were -- had not been pretreated with immune checkpoint inhibitors. All right. Now I'll transition and talk a little bit about our launch preparations at the company. This is our map of our authorized treatment centers or ATCs. You can see they're across the country, and they correspond in many cases with our clinical trial sites, which are green stars here so that we can take advantage of the knowledge of those sites. We're considering things like patient volume, NCCN status, KOLs, where they have a bone marrow transplant center or existing cell therapy capability, inpatient capacity, hospital bed capacity and Iovance clinical trial experience. And our goal is to basically drive the top account. We know that there's a curve with this where the majority of treatment will occur at a small number of centers in the country. So we know that if we target those centers first, will drive uptake much better. And we also have to work on what I call community referrals because a lot of the melanoma patients are out there in a community setting and they need to be referred to the larger treatment centers for therapy. Market access is a big thing for us. We were very successful with CMS and getting ourselves added to the MS DRG-018, which is a bundled treatment code that Medicare uses to pay for therapies. That was a big win for us, but we're also targeting the commercial payers. We've engaged with more than 90% of covered -- the payers responsible for more than 90% of covered lives right now. We've already got our ICD-10 PCS codes issued. Like I mentioned already, DRG-018 has been expanded to cover lifileucel. So we're feeling pretty good about our reimbursement landscape at the moment at the time we launch. All right. Now I'll talk a little bit about TIL therapy clinical program highlights. More deeper discussion on this is available on our website. If you want to see more, we can talk about it during the Q&A session. I'm just going to cover non-small cell lung quickly because it's one of our focus areas. The market for non-small cell lung in the United States, therapies are huge. There's a significant unmet medical need in the country right now for this. For example, in the second line setting right now, patients have access to something, all they have is things like docetaxel with a 9% to 13% ORR and very short durability. But you nevertheless, we've got millions of cases a year diagnosed and 130,000 deaths here in the United States from this. We are the only company right now in the TIL space that has shown compelling data in non-small cell lung. We've already gone to 28-patient dataset that we put out at SITC, where we showed a 21% ORR, including deep durable responses. The waterfall and the swimmers plot are shown here on this slide together. So we had 6 responders. These patients were heavily pretreated. They had 3, you can see 2 and 3 lines of therapy there. PD-L1 status was all over the place. We're not limited by PD-L1 status. We don't have some of the issues you see with some of the checkpoints. We've got long lasting durable responses at 18 and 37 months, with 37 months to ongoing in these patients. Now these are in the sickest possible non-small cell lung patients. So we've been focused on working on patients that are a little bit earlier in their disease as well as using additional products, including our IOV-4001 PD-1 knockout TIL product in this patient population to show whether we can improve durability and response. And by the way, I should mention on that slide, all these patients were -- I can't -- well, let me go back, but -- all of these patients were previously treated with both chemo and ICI, all the responders. So they all received everything you could throw at it, and they still were progressing and responded on TIL therapy. Let me talk for a few minutes about our next-generation research programs. First, we're working on genetically modifying TIL therapy. I already mentioned the PD-1 knockout, but we're working with Cellectis, a leader in gene editing, to do additional targets. Anything that you can knock out on the T-cell side. So TIGIT like CTLA-4 is of interest to us. We're working right now, especially on double knockouts to take advantage of some of the data we've seen with the bio-specifics and combinations that looks very promising. So double knockouts are a big area of focus for us in 2023, and hopefully, we'll talk more about that soon. We've also worked heavily with NCI and in-licensed a lot of technology around cytokine tethered TILs. So these are TILs that have on them a cytokine like IL-15 or IL-12 that will stimulate a broader immune response or maybe obviate the need for IL-2 co-therapy or both. So that's a big area of focus for us, and that's something that we hope to take to the clinic fairly soon. We're also working on developing more potent TILs. We have a PD-1 selected TIL product in the clinic right now. I didn't discuss that here, but that trial is running. And we've been working with Steven Rosenberg on CD39/69 double negative TILs, which he was -- he showed in the paper in Science about 2 years ago, correlate late with response. We're working on optimizing our process. We have a 16-day Gen 3 process, and we've got core biopsy process too. That's a process by which instead an excisional biopsy or surgery, we can actually use a small core to take a piece out of the tumor, it's less invasive, could expand TIL therapy to even more patients. So that's something we have in the clinic right now. And then we're also expanding into 2 new regimens. We've got an IL-2 analog from Novartis that can replace Proleukin, which is the therapy we use right now in combination with TILs. And that's an IND-enabling studies today. All right, some upcoming milestones. We intend to complete our rolling BLA submission this quarter, and we're looking to get FDA approval this year, and this is in the post-anti-PD-1 melanoma. We -- in the pipeline, we're going to enroll frontline advanced melanoma patients into our Phase III confirmatory trial. With non-small cell lung, we intend to report some data and continue to enroll our studies. We've got 3 separate studies running with multiple cohorts in each. So we've got plenty of opportunity here to put data out. In cervical, we're enrolling additional patients in our registrational Cohort 2. We've got our PD-1 inactivated TIL therapy in the clinic right now, and that's going to be in melanoma or is in melanoma and non-small cell lung and we're aiming to complete the Phase I safety portion and proceed to our Phase II portion of that study. And then finally, in research, we're moving more products to the clinic, including the genetically edited TIL therapies. In manufacturing, we're executing our GMP commercial readiness activities. We're getting ready for BLA approval, pre-licensing inspections, and we intend to be ready to supply lifileucel launch. We've watched the CAR-T companies very carefully and looked at some of their manufacturing challenges and made sure that we are upsized and ready for a significant demand to launch at our facility. We don't want to be one of these companies where we're trying to add manufacturing capacity with our hair on fire a year in after launch. We're going to get this right at the outset. And then finally, on the commercial side, we're preparing for and executing that commercial launch, particularly with onboarding the treatment centers. We've got a big team focused on that right now. A lot of treatment centers engaged, and we intend to, as we said publicly before, we intend to launch with at least 40 sites. All right. With that, I'll thank you for your attention. And I guess we can open the floor to questions.

Thank you, everyone. Just a reminder, if you have any questions, you can submit through online portal or you can raise your hand, the traditional way, and we are open for now Q&A. So we have our first question, Fred. Can you please comment on the design of Phase III study? What is the primary endpoint? What about OS? And does that need to be substantially enrolled by the time of filing with the FDA?

Yes. Let me kind of get over. Better way to do this. So we haven't disclosed the design yet of our Phase III study. That's coming very soon. Hopefully we can talk about that very soon, and that will include the endpoints and everything else that we think we have agreement with on the FDA. On having it substantially enrolled at the time of approval, that's not necessarily something FDA has said to us. Basically what they use is the term well underway. They want the trial to be well underway at the time of approval. And right now, we're very comfortable after discussing with FDA that we're going to be well underway at the time of approval.

Thanks, Fred. Any questions?

So what is the price tag if your drug get approved this year?

Well, that's something we would announce right after approval. But you can use the CAR-T therapies as sort of a yardstick for what we might price lifileucel at. And those are in the $400,000 range right now.

Okay. So how many patients do you expect to treat if that drug gets approved on a yearly basis?

Well, that's -- yes, so we haven't issued guidance on exactly what -- that would give you our revenue basically directly if we did that. But what we can say is we're looking to treat thousands of patients a year out of the gate. And so if you look at the size of that manufacturing facility, that's why it's built to go to 2,000 today.

You only have one manufacturer site, right, in the U.S.?

We have one site that we own, but we also, as a backup, have a contract manufacturing organization called WuXi, which also manufactures for us, and will be manufacturing for us, we anticipate will be manufacturing for us as part of our commercial strategy. So we announced last year that we have a commercial agreement with them. So some of the capacity will go to them and most of the capacity will sit with us, but that gives us some redundancy should something happen in one place or the other.