Inovio Pharmaceuticals, Inc. ($INO)

All right. Welcome back to the Citizens Life Science Conference. My name is Silvan Turkin, and I cover precision sciences at Citizens. It's my pleasure to host Jacqueline Shea, President and CEO of Inovio. Thank you so much.

Thank you so much, Silvan. It's a pleasure to be here today, and thanks for having us. So I'm going to kick off by just giving you a quick overview of Inovio. Those of you who are not familiar with the story. Just a quick normal looking forward-looking statements disclaimer slide that I'll be making some forward-looking statements during this presentation. So to provide you a quick overview of the company, we're a clinical stage biotech company. We're focused on developing and commercializing our DNA medicines to treat and protect people from HPV-related diseases, cancer and infectious diseases. We submitted our BLA for our lead program, INO-3107, and it's been accepted for review by FDA under the accelerated approval program. It's a potential treatment for a rare disease recurrent respiratory papillomatosis or RRP, which is caused by HPV types 6 and 11. We have a PDUFA target date, October 30 this year, and we have orphan drug and breakthrough therapy designations and orphan drug designation in the EU. We've requested a meeting with FDA to discuss some preliminary comments we received in the file acceptance letter related to eligibility for accelerated approval pathway, and we're not currently planning to seek approval under the traditional pathway. We continue to believe that the accelerated approval program is the best and fastest path to approval for 3107. We believe even with one product on the market, there's a significant remaining unmet medical need and significant market opportunity. We've currently established our commercial scale manufacturing for plasmids at CMOs, and we do our device manufacturing in-house. So 3107 is a combination product. It's a combination of both a DNA medicine drug as well as a delivery device to deliver it. And following on behind 3107, we have a deep clinical pipeline with multiple potential near and midterm catalysts. We recently announced a new collaboration with Akeso and the Dana-Farber Cancer Institute to evaluate a combination immunotherapy to treat glioblastoma in the Phase II INSIGhT trial. And we also have some very exciting next-gen therapeutics in earlier-stage development poised to enter clinical evaluation. So how do the DNA medicines work? Well, we start off by identifying the target gene that we either want to raise an immune response against or that we want to express to either produce monoclonal antibodies or to produce therapeutic proteins themselves. And then we use our proprietary algorithms to optimize those DNA sequences for expression. We clone those DNA sequences into circular molecules of DNA called plasmids. And then we're able to deliver those DNA plasmids into either skin or muscle cells using our proprietary delivery devices called CELLECTRA. Once they're in the skin or muscle cells, the DNA is transcribed to RNA, the RNA is translated into protein, and then the proteins can be secreted from the cell. Now these proteins can either drive an immune response. So in the case of 3107, we're really looking for them to drive a T cell response. They can also drive antibody and T cell responses for normal vaccine indications. And then as I mentioned, we can actually encode monoclonal antibodies within the DNA plasmids, have them assembled and then secreted from the cells into the circulation. And we can also produce potentially therapeutic proteins as well. So as you can see, this is a very versatile platform. So moving on then to our lead candidate, 3107 for RRP. To tell you a bit more about RRP. RRP is a rare disease. It's characterized by these small wart-like growth called papillomas that can form throughout the respiratory tract, but principally form around the larynx and the vocal cords. And that can make it very difficult to speak. It can make it difficult to swallow or even breathe. And in some cases, these papilloma can spread throughout the respiratory tract and into the lungs. It can become malignant and it can be a fatal disease. And we think that what leads to RRP is after you've had an infection with either HPV 6 or 11, there's an insufficient immune response, which really fails to clear the virus. And that's what leads to the cellular proliferation and the wart-like structures that form in the respiratory tract. It's a rare disease. Epidemiology suggests that there are about 14,000 active cases in the U.S., about 1.8 per 100,000 new cases annually. And you can get diagnosed with RRP at any age. There are kind of 3 peaks of disease instance around age 5 for pediatric RRP around age 30 and around age 60. And unfortunately, repeated surgery is the standard of care. If you can imagine your vocal cords, they're very delicate structures. They don't regenerate and they have to vibrate at hundreds of times a second for you to be able to talk. So surgery on these delicate structures is really challenging. And severe RRP can require hundreds of surgeries over your lifetime. So it's really a very difficult disease for patients and their caregivers to manage. And every surgery comes at a risk, the risk of the potential irreversible damage to the vocal cords and a cost in terms of impact to quality of life, preparing for recovering from surgery as well as the financial costs of a chronic disease. So 3107 is our DNA immunotherapy. It's designed to generate an antigen-specific T cell response against HPV 6 and HPV 11, the viruses that cause RRP. And in this way, it's really targeting the underlying cause of RRP. It's getting to that root cause rather than just continuing to cut away of the disease through repeated surgery. And what's really important to patients and what's really important in this disease is that every surgery matters to patients because the surgery in many ways is worse than the disease itself. And the cumulative risk for injury increases after every surgery. Ultimately, it only takes one surgery to irreversibly damage your vocal cords and damage your larynx. And after patients who have had about 10 surgeries, most of them will have had some irreversible damage to their vocal cords. So we believe, based on third-party market research that we potentially have the preferred product profile in the space. And that's based across 3 kinds -- 3 main elements: efficacy, tolerability and a simple patient-centric treatment regimen. In terms of efficacy, we saw an improving response over time. We saw a good response in the first year after treatment of 72% of patients seeing between a 50% and 100% reduction in surgery compared to the year prior to treatment. And this rate improved into the second year and went up to 86% in year 2. And in terms of complete response, so these are patients who required no surgeries at all. We saw 28% of patients in year 1 requiring no surgeries, 50% in year 2. And what physicians tell us is really meaningful is that this means that for their patients, 3107 is very likely to help reduce the number of surgeries that their patients need, which is what -- exactly what they're looking for. And because we don't require any scoping or surgeries during the dosing regimen, it comes without that added risk. In terms of tolerability, 3107 treatment was very well tolerated. The most common adverse events were transient injection site pain in about 30% of participants, a little bit of fatigue. Very importantly, we didn't see any discontinuations. And when physicians look at this tolerability profile, they think it's good. They think this means that their patients will be able to get back to work quickly. And that's important, especially when patients are receiving multiple doses over a relatively short time frame and have been managing a chronic disease. 3107 is able to be administered in the doctor's office. The CELLECTRA device is very easy to use. Any health care professional can be trained to deliver 3107. And there is no requirement for scoping or surgeries during the dosing window. And that's really important to patients because they're not being exposed to additional surgeries. So in the near term, we're really focused on delivering 3107 to patients. As I mentioned, our BLA has been accepted under the accelerated approval program. We have a PDUFA date in October. We have requested a meeting with FDA to discuss their preliminary comments in the file acceptance letter. And we believe that we have the potential to have the preferred product profile in this space if approved. Following on behind 3107, we have some other exciting candidates, 5401 in combination with Akeso's PD-1/CTLA-4 drug. 3112 in combination with Coherus LOQTORZI in HPV-related throat cancer. These candidates are both T cell-based. And then our dMAb candidates where we published our proof-of-concept clinical data from our Phase I study showing that we're able to produce monoclonal in the body for therapeutic levels that are stable and out to -- and at therapeutic levels out to 72 weeks, which is very exciting. And then moving on to our next-generation candidates. We're starting to use this ability to produce proteins within the body to start going after protein replacement diseases. And we presented our first preclinical data for Factor VIII production in hemophilia last autumn. Now I think we are going into a quick fireside chat. Thank you.

Thanks for the presentation. Maybe you'll just drill down a little bit more on the regulatory interactions that you had and what is to come. So the FDA came back to you saying accelerated approval may or may not be open to you. What is the -- what's your view on this? And what's the case that you're going to make in front of them in this meeting that's coming up outlining why it should be open to you?

Yes, great question. So let's go back to the beginning, perhaps and see how we got to this point. So we completed our rolling submission of our BLA under the accelerated approval program in October last year. The FDA accepted our BLA under the accelerated approval program in late December. But instead of the priority review, we'd asked for, they granted us a standard review. And we also got a comment in the final notification letter about a potential review issue, so just potential at this stage. And it was a preliminary comment that at that time, we hadn't provided sufficient or adequate information to justify review under the accelerated approval program. So in January, we asked FDA for a meeting. FDA came back and said they were willing to meet, but they asked us to complete an assessment aid. And then an assessment aid is really a document that allows us to put forth our case and our rationale in quite a lot of detail as to why we think we're eligible for approval under the accelerated approval program as well as some other clinical and other data that they asked for. So we submitted that assessment aid in February, and we're now waiting for FDA to schedule the meeting.

So we hear, right? I mean it's hard to interpret what you hear from the FDA and you don't want to speak for them, right? But it seems like they just want to help additional information to make the case for cellular approval rather than being against the cellular approval and you have to convince them otherwise. Is that correct or...

Well, the final notification letter was the first indication that we've had from FDA that they had any concerns about eligibility under the accelerated approval program. We do very strongly believe that we are eligible for review under that program. We have made the case and the assessment aid, and we're looking forward to our meeting with FDA. And if I can just briefly comment on our rationale. The guidelines are very clear for accelerated approval. You have to provide a meaningful therapeutic benefit over existing treatments and you have to meet an unmet need. We believe that we do this by having an improved safety profile. Unlike the approved product, we don't require scoping or surgeries during the dosing window, which gives us a better safety profile, we believe. And we also have a differentiated mechanism of action. So the approved product is an gorilla adenoviral-based product. And that means that it can be impacted by neutralizing antibodies that can be preexisting in the population or that can be formed during the treatment regimen itself. As we're not an adenovirus, we don't have that issue. And it also -- and we also have a differentiated mechanism in that the approved product, they published data that shows that certain elements of the papilloma microenvironment restrict their efficacy. We tested the same elements, and we didn't see any restriction in our efficacy. So part of this, we think, is due to the fact that we're delivering via DNA and not by an adenovirus. So we think the 2 products are very different. There's clearly an unmet need. Papzimeos doesn't meet the needs of all patients. And we think we have a strong rationale for review under the accelerated approval program.

Great. And needless to say, the review of Papzimeos was abbreviated by the FDA creating the situation in the first place. So I would think that they would be a little bit open to such requests. Maybe talking -- I might have missed this, but outside of the FDA, for example, EMEA or other regions, what's your progress there for and your thinking about filing?

Yes. So we've gone and received scientific advice from CHMP in Europe. We've also discussed with the U.K. regulators. So we have orphan drug designation in Europe. We have ILAP designation in the U.K. We also have ATMP designation in Europe as well, which basically means that they've looked at our clinical data package and our preclinical data and agreed that it meets the -- and CMC data and agreed that it meets the standards required for submission. However, the feedback that we received from the European regulators was quite different from FDA. They're really looking for placebo-controlled data, and they're really looking for data from 2 efficacy trials. So we're going to continue our interactions with the European regulators, but 2 very different regulatory feedbacks.

And you mentioned that you're currently not looking at a Phase III controlled trial, right, that could turn off...

If we're -- obviously, if we continue down the accelerated approval pathway, we will need to conduct a confirmatory trial. And we have put in an amendment to our IND for the confirmatory trial, and we hope to finalize the design of that confirmatory trial with FDA as part of these discussions.

Great. Maybe shifting a little bit, and you've touched upon some of these things already, I think, when you were saying for the case for accelerated approval. But how -- given that the Papzimeos is approved out there, how are you thinking about differentiation with the data that you have today, maybe from a patient's perspective and also the practitioner's perspective?

Yes. I mean, obviously, as a second market entrant, it's going to be very important that we have an efficient launch. But I think what's really key to the opportunity here for us is our differentiated product profile. And we do think we have the ability to have a preferred product profile in the space. And this is based across the efficacy, also across the fact that we have an improved safety profile and that the product can be given in the doctor's office. And when you compare this to the approved product, the approved product needs these scoping and minimal residual disease surgeries if disease is present at doses 3 and 4. It also requires an ultracold chain. So that makes it more difficult to be given in the doctor's office. We're waiting to hear actually how -- what channels Papzimeos is actually being given through, but it makes it more challenging. And obviously, in terms of the patient, knowing that they're not going to have additional surgeries during the treatment regimen, it's very attractive to them.

On average, how many do they have as of today? I mean, the launch is quite early, but how many fewer surgeries would they have with your product on average? And maybe if you can comment around the burden that each of these surgeries has for the patient? How long does it take the patient to heal? Or would this patient be out of commission?

Yes. So let's start by talking about the surgeries. So most of the surgeries, as you can imagine, your vocal cords, it's very hard to do these under local anesthetic. It's possible in some cases to do the laser under local anesthetic just in the doctor's office. But the majority of these surgeries require general anesthetic. And the recovery from these surgeries can be really difficult. In some cases, patients have to go on a liquid diet. They have to be on voice rest for weeks. And even after that voice rest, their speaking voice can be impacted. So it's actually a really challenging surgery for patients to recover from, very painful surgery as well. So in terms of differentiation between the 2 products, for the Papzimeos product based on their published data, 83% of their patients required 1 or 2 surgeries during the dosing window. And of their complete responders, 72% of their complete responders required surgery. So in comparison, none of our complete responders required surgery during the treatment window. And that's really -- and the impact on the safety profile, I think, is really a key difference between the 2 products.

Great. Maybe on the manufacturing side, how is this product being manufactured? And who does that for you? And where is that with respect to a potential launch in October?

Yes. So as this is a rare disease, it's not a huge amount of product, obviously, to manufacture. So we manufacture our plasmids at contract manufacturers that have been FDA and inspected and approved. We produce the drug substance with one manufacturer, and then we fill the final product with a different manufacturer. In terms of assembly of the device, we are buying components and then we assemble the devices ourselves in-house. And we have CE marking for our 5PSP device in Europe. So in Europe, it's already regarded as a commercial-grade device. But here in the U.S., we're regulated as a combination product. So both the drug and the device have to be approved together.

Okay. And that was with the PDUFA in October.

Yes. Exactly.

And then you presented one slide on kind of some of the, I guess, survey activities you're doing. But like overall, what are some of the pre-commercial activities that you're currently running ahead of PDUFA?

Yes. So we were clearly preparing for a PDUFA date midyear. So we're well underway with our commercial preparations. So we've conducted critical market research. We are now conducting a price optimization research as well now that the Papzimeos price is established. And on the operational side, we really have all of our core pieces in place. So we have our 3PL, third-party logistics provider on board, our channel distribution partners identified, our patient hub partners identified. And we also are working, obviously, with our agency of record around the promotional materials, et cetera. So we're really pretty advanced in terms of our commercial preparations. We haven't put people really in field yet. Obviously, we're looking to get this issue with the FDA resolved first.

And what kind of sales force do you need? And how should we think about the ramp of spending if there's a launch?

Yes. So this is a very concentrated market. We estimate between 300 to 400 laryngologists treat the majority of RRP patients. So it's not -- you don't really need a very big field force to help support that size of market. I think Precigen have said they've got somewhere in the order of 18 to 20 sales representatives. So it's not a big field force that we're looking for.

And I'm sure you've touched base with a lot of laryngologists. What's some of the feedback on your product while they presumably maybe taking a look at Papzimeos. Do they understand the difference? Is there anything that you can say?

Yes. First of all, I would say laryngologists clearly see the need for therapeutic alternatives to surgery for their patients. The disease really places a heavy burden on their patients. They don't like doing these surgeries because they're repeated, they're not curative. And so they're really looking for a therapeutic alternative. When they look at the 2 different product profiles, as I commented, I think they see the reduction in surgery that we've demonstrated where they can say to their patients, you are likely to see a substantial reduction in surgery or even require no surgeries at all. That's very attractive. The ability to use 3107 in the doctor's office, not have to refer those patients out to the infusion center, et cetera, that's also very attractive to them. And then the other logistical issues of not having to schedule scoping and potential surgeries. And remember, the majority of patients who received Papzimeos in their clinical trial required surgery as part of the dosing window. So the fact that they don't need to schedule the scoping and these surgeries as part of the treatment regimen is also relieves the logistical burden from them.

Good. And obviously, all eyes are presumably on this asset and how the interactions go with the FDA. But within your pipeline, you have a partnership with Akeso that you mentioned and some others and then obviously, the antibodies further back, like what is something you want to point investors to being like, hey, we also have this going on in the background?

Yes. So clearly, our ability to drive T cell -- antigen-specific T cell production is really, really strong. And that's what's underpinning 3107, 5401, 3112. And these are exciting assets. We're really pleased with the partnership with Akeso to move 5412 forward. But at the moment, we're having to focus the majority of our assets towards 3107. We're also looking to move forward some of our earlier-stage therapeutic protein preclinical programs forward, some of our dMAb programs forward. And we're primarily looking to move this forward in partnerships -- so lots of exciting stuff going on at Inovio. T cells closest to approval. But I think the dMAb and the DPROT technology is truly groundbreaking and very exciting. And with the clinical data that we published last year, we're getting some good interest now on the partner side.

Great. Well, thanks so much for joining us today, and thanks for your insights.

Thanks very much for having us. Thank you.