Let's get started and welcome back everyone to the 2024 RBC Global Healthcare Conference. My name is Greg Renza, one of the biotechnology research analysts here at RBC, and we're pleased to be joined with INOVIO Pharmaceuticals now. And joining us from the company is the Chief Executive Officer, Jacqueline Shea. Jackie, it's great to see you. And Mike Sumner, the Chief Medical Officer. Guys, great, great, great to see you, and certainly a lot going on with Inovio, and you've have been heads down in execution, and maybe to an extent in a company reinvention. I think that's worth talking about. Maybe Jackie, we could just start for those who aren't as familiar with Inovio story, to just give us a brief intro to the company and an update on the latest with the pipeline. Yeah, thanks, Greg, and thanks for having us. So INOVIO is a clinical stage biotechnology company, developing DNA medicines against HPV-related diseases, oncology, and infectious disease indications. Our DNA medicines platform allows us to express proteins within the body's own cells, which can either drive an immune response that can be protective or therapeutic, or can be the therapeutic agent itself. Over the past couple of years, since I became CEO in May 2022, I've really been focused on three core aspects. First of all, driving our lead program, INO-3107, for treatment of RRP or recurrent respiratory papillomatosis forward. We reported a very positive phase I and II data last year, received Breakthrough Therapy Designation, and the FDA approached us and told us that our clinical data was sufficient to file a BLA under the Accelerated Approval Pathway. We're looking forward to filing our BLA in the second half of this year, and potentially, depending on the timelines, launching INO-3107 in 2025. So very exciting time for the company. And then secondly, following on behind INO-3107, we have a deep pipeline of other clinical stage assets, in particular, INO-3112, which we're developing for the treatment of HPV-related oropharyngeal squamous cell carcinoma, also known as throat cancer. We're looking to start a phase III trial there, and that would be a combination of INO-3112 in combination with Coherus BioSciences PD-1 inhibitor LOQTORZI, which was recently approved for treatment of nasopharyngeal carcinoma here in the U.S. And then finally, I've been very focused in terms of, as you talked about a turnaround. It's been more about, I think, really focusing on the strengths of the platform, really doing some pipeline prioritization, and really going after those programs that we think meet a high unmet medical need, have a good regulatory path to market, and also have strong commercial potential. And that's really what we've been focused on. And in many respects, RRP fits the dimensions that you're commenting on, the commercial attractiveness, but of course, the unmet need. And as you've made pipeline prioritization and those important decisions, you know, INO-3107 has climbed to the top with respect to the data. Let's talk about the opportunity. There is a degree of maybe under appreciation or explication that this market requires. So let's start a bit with the pathophysiology, the benefits of surgical avoidance, and maybe even some of the numbers, so we can actually get a sense of what we're going after with the INO-3107. Yeah, that's a really important question. So with a rare disease, unfortunately, there isn't always the awareness of what RRP is, and what it means to patients, and the impact that it has on patients' life. So the key is in the name, recurrent. So RRP is a disease caused by HPV 6 and 11 subtypes. And what happens is you get growths of these wart-like structures in the respiratory tract, particularly on the vocal cords, and that really impacts people's quality of voice. They can lose the ability to talk clearly, it can be difficult to breathe, it can be difficult to swallow, and the only treatment is repeated surgery. And the surgery itself really isn't the solution because it can damage the vocal cords, and the vocal cords are very fine, delicate tissues. They don't regenerate. They have to vibrate hundreds of times a second to enable you to talk. So as you can imagine, repeated surgery on these delicate tissues, it's a difficult surgery to do, and the potential for damage is really pretty high. While RRP is a rare disease, it's not that rare. So there are about 14,000 prevalent cases we believe in the U.S., and about 1.8 per 100,000 new cases a year. And there are generally three peaks and incidents across the different ages. Pediatric RRP tends to peak at around age seven, and then adult RRP tends to peak in the mid to late 30s, and then there's another peak in the early 60s. So this is really a chronic lifelong disease, really in desperate need for a therapeutic alternative to surgery. Can you touch a bit just on that patient journey, so we do have that appreciation for how impairing and limiting the surgeries are. It's certainly helpful to hear about the trimodality of the ages, but also within a specific recurrence, that there's a great deal of care management that is complex and the journey is not always intuitive. Maybe just touch on that, and then we'll get into where- we're certainly INO-3107 Yeah. Gets in to solve for that. I think I'll ask Mike to talk to that. So I think it's, as Jackie said, I mean, it all comes down to the impact of one surgery. I mean, certainly, these patients are very readily diagnosed, and certainly in adulthood, when usually the symptoms start with the voice. You know, as soon as anybody has their voice impacted for two weeks, they're going to go out and seek medical treatment to get that diagnosis. You hear from the RRP Foundation that a reduction in just one surgery matters, and that took me a little while to sort of comprehend because it's very easy to say, "Oh, just one surgery, what does that mean?" But then coming back to the fragility of the vocal cords, you know, there's data out that came out from Simon Best, from Johns Hopkins, and patients who had had less than five surgeries had a 44% chance of permanent damage to their vocal cords. So it just shows how easy it is that one surgery can cause that damage. And you don't know whether it's gonna be your first surgery. It's certainly already going to have happened when some of these patients have had sort of hundreds of surgeries over their lifetime. There's no way they aren't having permanent damage to their vocal cords. So that one surgery really does make a difference. And so you think then of our phase I/II data and what we actually saw. We saw an 81% reduction in surgeries in our phase I/II study. 28% of those patients had no surgeries whatsoever in the year that we followed them up. And when you look at our partial responders, the vast majority of those we're actually seeing a greater than 50% reduction. So we really are having a significant impact on this patient population, and it all comes back to what that one surgery means. Mm. And on average, how many surgeries were those enrolling? Just talk a bit about the baseline characteristics to get a sense of where we're starting from. It's an important point. In addition, just going down to, as you said, some patients just no surgeries at all. Yeah. So the average number or median number of surgeries in RRP patients is roughly four per year, and that was similar in our trial. So we enrolled 32 patients in our phase I, II trial. The median number of surgeries before intervention was four per year, and then after our intervention with 310 7 across the whole 32 patients, we saw a median reduction of three surgeries. So as you can see, we were vastly reducing the burden of surgery. And can you put the like the safety profile into context, and it might be a nice pivot to get into your FDA discussions and the plans for filing on the confirmatory. But I think in many respects, we don't talk about the safety profile that really is the grounds for these programs to begin with. Yeah, absolutely. And it's one of the, I think, one of the strengths of Inovio's data that we have. I mean, we've actually, we're getting close on 18,000, you know, plasmid administrations, and when you look specifically at intramuscular, we're close to 6,000 administrations. Well over 1,000 of them are actually with our commercial device, 5PSP. And so what we tend to see is there is some temporary discomfort associated with the administration, but then following that, you don't get the same sort of viral symptoms that you associate with vaccines. And in fact, the adverse event profile is virtually indistinguishable from placebo. We have our data from our phase III program with 3,100, so we actually have a very nice database to look from a safety profile. So that, I think, is one of our strengths as we go into the regulatory process, because obviously, everything starts from first do no harm. So having that safety data is, I think, a tremendous benefit for us going into the accelerated approval process. Where are you with the FDA discussions, having the...? We have some details on the confirmatory trial, but for the audience, what step are we at when it comes to the FDA interface? So we've made full use of our Breakthrough Therapy Designation. I mean, it really has given us an opportunity to engage with the FDA all through the regulatory process. And so I think we have a very good understanding of what they're expecting to see in the BLA. We're still on track to get that BLA submitted in the second half of this year. And we've made significant advance with the confirmatory study. And as you know, we were in discussions with the FDA to run a phase III study prior to the call when they said we could, you know, file with our current data. So we have our CRO. We'd already started looking for clinical sites. We have the vast majority of those identified. So with the alignment on the FDA of the actual design, we're moving rapidly to get the study up and running. So that certainly won't be a roadblock for us to be able to submit our BLA. What are some of the key features of that confirmatory design? Yeah, so we settled on a randomized, placebo-controlled study, and the rationale for that was really twofold. We heard from the FDA that if we wanted an indication, a future indication, hopefully of two or more surgeries, it had to be a placebo-controlled study. And the other aspect is we've started our discussions with the European regulators, and they were very clear that, you know, to get approval in Europe, it needed to be placebo-controlled data to do that. So, you know, obviously, HPV is a global disease. We didn't just want to limit the benefit of INO-3107 to the United States, so having a clinical package that was going to be suitable for global registration was important for us. Mm-hmm. Great. If I can just add there, in our original phase I/II trial, we enrolled a broad spectrum of patients. So we enrolled patients who'd had between two-eight surgeries in the year prior. We also enrolled patients who'd had HPV 6-related disease, HPV 11-related disease, as well as a mixture of HPV 6 and 11. And I'm pleased to say we saw efficacy across the spectrum of disease, across both HPV 6 and HPV 11. And working within that phase I/II clinical trial, we worked across 8 different clinical sites, and again, our efficacy signal stood up regardless of investigator, which clinical site. So we really think that our phase I/II data is very representative and is going to stand us in good stead as we go into this confirmatory trial. Great. Great. And I think some investors have keyed in on the potential or the aspect of repeat dosing. Jack, to your point of recurrent, it's the first R, and maybe some or many have not. So, maybe share just some of the thinking on repeat dosing, the philosophy there, and also the potential presence in the trials. Well. So, I mean, one of the hallmarks we think of our DNA medicine platform is repeat dosing. We've done this numerous times in other disease states. Some of our oncology patients are actually going on five years and still receiving treatment. So we know that we can continue generation of that, the CD8 cells, which are so important in this disease. And so the initial focus is really going to be on looking at those partial responders and the non-responders and seeing if we can change their immune response to the initial course of therapy. And we announced this week, we're actually going to be publishing some of their immunology data in the second half of this year. And I think that's given us really good insight in what we need to look for in these patients. Hopefully, we'll get a very early readout once we start being able to dose these patients and seeing if we're able to change their trajectory of their disease. Yeah. I think it's really important to note that RRP is really a disease of having a defective immune response, because the majority of people can clear HPV 6 and HPV 11. And in these RRP patients, something is going awry with their immune response. They're not able to clear the virus, and this is why they have this chronic, often lifelong infection. So what we're doing with INO-3107 is we're generating these highly activated antigen-specific CD8 T cells in the periphery, and then they're having their clinical benefit by potentially destroying HPV-infected cells in respiratory tract. And this is very similar to what we've seen across other indications as well, in HPV-related diseases. When it comes to actually extracting the full value proposition of INO-3107, what's the latest on reimbursement potential? What's the framework that we should be thinking about, that you're thinking about? And certainly, when it comes to the baseline of cost avoidance and surgery avoidance, our sense is it just starts there. How should we flesh out a framework for thinking about not just pricing, but just the value proposition? Yeah. So I think it's still a little early to talk about pricing, but in terms of the value that INO-3107 can potentially add for patients, physicians, and payers, it really is about the avoidance of that surgery and the avoidance of permanent damage to the vocal cords. I think it's also important to note that with RRP, it can spread into the lungs, it can become malignant. Now, these are small percentage cases, but the longer you have RRP for, the risk of that goes up as well. So in addition to the incredible physical and emotional burden on patients of having to go through these repeated surgeries, there's also that risk of the disease worsening as well, that we're having to deal with. And I, I think, you know, potentially a good example in this space is, is another rare disease, desmoid tumors, where just last year, nirogacestat was approved by the FDA for treatment of, of desmoid tumors. There are some similarities, as an analog with RRP, in that, again, this is a, rarely fatal disease, requires repeated surgery, which really doesn't solve the problem. So I think, you know, that's a good example of, where a therapy can come in and really make a difference in a rare disease treatment space. Yeah, that's an important analog to think about beyond RRP. And within the RRP landscape, other programs under development, so there's certainly some spotlights that are shining on RRP. How do you break down the developmental landscape and how INO-3107 fits in? Certainly, there are differences in the studies thus far. There are differences in administration and differences perhaps in strategy, too. What is your view on the landscape? ...Yeah, that's a great question. So when we're thinking about INO-3107, we're really thinking about how can INO-3107 help the broader spectrum of patients? And that's really why we're focused on the spectrum of disease from two to eight. We've been focused on HPV 6 and 11. We have plasmids encoding for, or proteins from both HPV 6 and 11. And also, you know, I think it's very important to note the sort of broad effect that we saw in our phase I/II trial, where we saw 81% of patients had a reduction, and 28% of those patients required no surgery at all after day zero. We counted all surgeries after day zero, so even in the dosing window, because every surgery matters to patients, and every surgery is, it's a potential for damage to the vocal cords. And I think the other sort of important things to bear in mind is INO-3107 is refrigerator stable. The device itself is very tolerable for patients, as Mike talked about. It's very easy to use by healthcare providers. The device is composed of two components. One is a handset, one is a sterile use disposable nozzle. We insert the drug cartridge into the nozzle, attach it to the handset, apply it to the arm, and then it's just a single button trigger, and the drug is delivered by the device in seconds, and the whole process is done in minutes. And I think we also have to remember that the people who will be using this are laryngologists or nurses, et cetera, other healthcare providers in laryngologists' offices. They're very used to using devices, and this is actually a very easy-to-use device that's been seen by a lot of regulators around the world, and we've worked with a lot of different clinical groups around the world. We've had very positive feedback from them on how easy the device is to use. And as far as INOVIO's ability to meet supply for not just the confirmatory, but also for commercial launch, how should we think about the capabilities that you're laying down in order to meet commercial and clinical demand? Yeah, great question. So actually, we think this market is a really good size for a biotech like Inovio to take on ourselves in the U.S., in terms of the number of patients. We were already at commercial scale manufacture in terms of our plasmid manufacture. Each run can generate tens of thousands of doses, so we actually only need a couple of manufacturing lots per year to supply the entire market. And then we manufacture our devices and our single-use disposable arrays ourselves in-house, and we have more than enough manufacturing capacity to support that. Okay, great. And you comment on the receptivity broadly from regulatory bodies. Just remind us on the European designations, and also what work is left with on the stateside, when it comes to acceptance in the package for the device, along with the drug. Mike? Yeah, certainly. So, starting off with Europe, we have orphan designation, and we also have CE Marking for our device. So we're in a good position to move forward with those discussions. When it comes to our file in the United States, obviously, we've already completed our clinical data, and we have our other safety data that will be included to support the package. The FDA obviously do not, you know... Just because we're under accelerated approval, we still have to meet all the normal non-clinical CMC elements of our file, and the device is an ever-changing environment, so making sure that we meet all our guidelines. Everything, as I said, you know, we've planned it all out very carefully, and everything is on track for that second half of the BLA submission. Great. Great. Yeah. I'd just like to summarize really by saying it, you know, we're very pleased with the data we've seen with INO-3107. We believe that it has the potential to be the preferred product for patients with RRP, and we're really focused on getting that confirmatory trial started and getting our BLA submitted this year. Launch preparations and planning are well underway in terms of being able to successfully launch INO-3107. Great. Great, and maybe just as a closing question for your remarks, while the focus is certainly on 3107, you brought up 3112 and the pipeline. So maybe just lay out some of the things we should be watching on that program. Yeah. So, for 3112, we announced the collaboration with Coherus at the beginning of the year. As I mentioned, we've had some very promising discussions with the FDA on our phase III design. We're now gonna take that phase III design and go and discuss it with European regulators. Our plan is to conduct this trial across both North America and Europe, and we're going to be in the locally, regionally advanced space. So we're not playing in the recurrent metastatic space, it's locally, regionally advanced. And we're going after the high risk, HPV 16 and 18 associated disease, where these patients have a high risk of reoccurrence, and currently, there are no treatment options for them. They're on watch and wait. To be able to offer a therapy that would reduce their risk of recurrence, we think would be really meaningful in this space. Great. Good place to leave it. Jackie, Mike, great to see you. Thanks. Thanks for all the updates. Thank you. Thanks, Ben. Thank you for joining us.