Presenting company. We are here with INOVIO, represented by Jacky Shea, the company's President and CEO. My name is Eric Schmidt. I am one of the biotechnology analysts at Cantor Fitzgerald, and I am sharing this fireside chat with my colleague, Alexa Diemer. Jacky, thank you for coming. Maybe just high level, I know you have got an important FDA action date coming around the corner, which we are going to get into, but for those less familiar with INOVIO, what are the two-minute highlights?
Yeah. Well, first of all, thanks very much for the invitation. It is nice to be here today. INOVIO is a clinical stage company. We are focused on developing DNA medicines to help treat and prevent HPV related diseases, cancer, and infectious diseases. As Eric mentioned, we have got a very exciting PDUFA date coming up in a few weeks time, on 30th of October for our lead program, which is INO-3107, for the treatment of recurrent respiratory papillomatosis or RRP. Following on behind that, also based on our DNA medicines platform, we have a deep clinical pipeline of other candidates.
Tell us a little bit more about your DNA medicines platform, what that means, what that entails.
Yeah. DNA medicines have been around for quite a while, and what makes INOVIO different is really our delivery system. We start off by identifying target proteins that we want to produce within the body. We then optimize them using our proprietary algorithms, and then we insert the optimized sequence into a circular molecule of DNA called a plasmid. Then we use our proprietary delivery system called CELLECTRA to enable the DNA plasmids to enter the cells. CELLECTRA works by very brief electrical pulses, which open pores in the cell membrane and allow the DNA plasmids to enter the cell, and then the pores close back up again. These are really rapid electrical pulses, millisecond pulses.
Once the plasmids are in the cell, they are transcribed into mRNA, then translated into protein, and then depending on how we've designed the protein, they can either be secreted from the cell or processed within the cell for antigen presentation. Our DNA medicines platform is very flexible. We can produce pretty much any kind of protein, and then we can use that protein to either drive an immune response. DNA medicine is particularly good at driving T- cell responses, which is important for treating cancer and virally mediated diseases. It is also very good at producing sustained protein levels. This is particularly good for treating diseases where you've got a missing or a defective protein and you need to supply that protein. Those are really the core advantages of the platform.
The CELLECTRA device. How is that delivered? What is the patient experience going through that? Tell us a little bit more about.
Yeah.
What it looks like.
We use our CELLECTRA devices to either deliver our DNA medicines to either skin or muscle cells. With the muscle cells, it is pretty similar to an IM injection, but then followed by these rapid electrical pulses, which enable the DNA plasmids to enter the cell. It is a very simple, straightforward administration. Our device consists of a base station, a handset, a single use disposable needle array. You insert the plasmid drug cassette into the single use needle array, attach it to the handset, remove the safety cap, apply it to the deltoid muscle that you previously used an alcohol wipe on, and then it is a single button press. That injects the plasmid, delivers the electrical pulses, whole process is over in seconds.
Any healthcare provider can be trained to use it, and patients tell us whilst there is mild to moderate injection site discomfort, that resolves pretty quickly within 5- 10 minutes. Patients tell us overall, it's a very tolerable process. A key thing about DNA medicines though is unlike other T- cell generating approaches like viral vectors, you don't get the systemic kind of responses, systemic flu-like symptoms that you can get with other systems. After the injection site discomfort resolves, we really see very, very few adverse events.
We'll talk about the lead program, INO-3107 for RRP in a moment, but does the device itself require approval concomitantly?
That really depends on the territory. In the U.S., it's regulated as a combination product, so it doesn't have a separate approval. Ex U.S., the device can be regulated independent. For instance, in the E.U., we have CE marking for the device already.
Okay. Sticking with the high level, as we start to dive down into the story, what do you think investors are missing about INOVIO today?
Yeah. I think investors are perhaps not quite appreciating how close we are to bringing the first DNA medicine potentially to approval and commercialization, and then the deep pipeline that follows behind based on the platform. I think we have a lot of exciting potential catalysts coming up.
Your DNA medicines platform could, I guess, in theory, go into so many different directions, and I know over the course of the company's history you've investigated a few different things. Why is RRP the right opportunity, and what are other kind of landscaping exercises you've been through to land here?
Yeah. I think RRP is really a great opportunity for DNA medicines because it's really leveraging a core strength of the platform, this ability to generate antigen-specific T- cells that can go after the virus that causes RRP. RRP is caused by HPV 6 and HPV 11. INOVIO has had a long history of working in the HPV space, and we've demonstrated the ability to eliminate the virus in other HPV-related indications. It was a combination of our expertise in HPV treatment, a disease with really high unmet need as well, and then really leveraging this ability to drive the strong T- cell response.
How are patients with RRP managed today? Maybe you can elaborate a little bit more on what the unmet need is.
Yeah. To tell you a bit more about RRP, because it's a rare disease and everybody may not be familiar with it, RRP is caused by HPV types HPV 6 and HPV 11. You can get disease throughout the respiratory tract, but it mainly forms around the vocal cords. What happens is you get the growth of these wart-like papillomas on the vocal cords. It can make it very difficult to talk, swallow, breathe. In some cases, RRP can spread throughout the respiratory tract, go to the lungs, and become malignant. In those cases, the outcomes are pretty poor. Treatment today, or standard of care today, really remains surgical reduction of the papilloma, either by laser or by scalpel. Because you can't cut a virus out with a scalpel, these papilloma grow back time after time, hence the name recurrent respiratory papillomatosis. These surgeries, they're not curative.
They're not eradicating the virus. The problem is the surgeries themselves come with a risk to the patients, and the risk is permanent damage and scarring of the vocal cords and of the respiratory tract tissues. That scarring in itself can lead to future surgeries as well. It's a horrible cycle of disease, surgery, more surgery.
Just so maybe we can understand the burden of the current standard of care, on average, how many surgeries would you say that patients get per year?
Yeah. There's not a lot of data out there. We enroll patients who'd have between two and eight surgeries in the prior year into our clinical trial, and we think that's pretty representative of the population with active disease. On average, about four surgeries a year.
Okay. Maybe now you can walk us through the phase I/II trial. What was the study design, patient population, enrollment criteria? What endpoints did you evaluate and what the data showed? Maybe you can also comment how the data compared to your initial expectations.
Yeah. I think the first thing to bear in mind is what patients are most concerned about is reducing the number of surgeries. Because each surgery comes with this risk of permanent vocal cord damage. That is what they are really focused on. We designed our clinical trial with that in mind. What we were doing is really looking for a reduction in surgery. This was a phase I/II trial, 32 patients. We enrolled patients who had had between two to eight surgeries in the year prior, and we enrolled patients who had either been diagnosed with HPV 6, HPV 11, or a combination of the two serotypes. They had to have had confirmed HPV 6 or HPV 11 disease before trial entry.
Our regimen is when patients required a clinically required surgery, they had that surgery, they entered into the trial, and then we gave them 4 doses over a nine-week time period, so 1 dose every three weeks. It is very important to note that we counted every surgery after day zero because, as I have said, every surgery matters to patients. We were really pleased with what we saw. In the first year following treatment, 72% of the patients experienced a 50%-100% reduction compared to the year prior. This clinical efficacy strengthened into year two, where that figure went up to 86%. If we look at patients who required no surgeries during year one, that figure was 28%, strengthening into 50% in year two. We saw a really good clinical response. We were really pleased with that.
I guess maybe taking a step back, you said that patients needed to either have HPV 6, HPV 11, or both. What percentage of RRP patients are either HPV 6, HPV 11, or both?
Yep. It's estimated over 95% of RRP patients are HPV 6 or HPV 11. The majority of the disease, about two-thirds, is HPV 6. HPV 11 is actually potentially correlated with a slightly worse disease course, and then some unfortunate patients have both serotypes.
Okay. You commented on the very impressive efficacy profile. Maybe now you can elaborate a little bit more on safety and tolerability.
Yeah. We were really pleased with the safety and tolerability profile we saw. Mainly grade one, two adverse events, very few systemic events. With DNA medicines, we really don't see the flu-like symptoms that you see, for instance, with viral vectors.
Okay, got it. The BLA was submitted under the accelerated approval pathway, but then the FDA flagged that the data package may not be adequately eligible for the accelerated approval pathway. Maybe you can comment on what the company's done since then to strengthen the case and where things stand today.
Yep. I think it really goes back to the fact that there was a product previously approved last year. When you have a previously approved product that has a full approval, under accelerated approval, you have to do two things. You have to show that there is a continued unmet need, then you have to show that you provide a meaningful therapeutic benefit over the available treatment. We think we have done exactly that through INO-3107's efficacy, tolerability, and a patient-centric treatment approach. What I mean by that is the currently approved product, it does not work in all patients, it also requires surgery as part of their treatment regimen. Over their 12-week treatment regimen, they scoped their patients at doses three and four, and if visible papilloma were present, those papilloma had to be removed.
In contrast, with 3107, we do not require these scoping and surgeries at doses three and four. We have a significant safety advantage because we are not requiring those additional surgeries as part of the treatment regimen. We are also using different antigens as well. Because of the different delivery systems, we are not impacted by pre-existing neutralizing antibodies or the papilloma microenvironment. We believe that we can treat patients that Papillomavirus does not work in.
Did the FDA ever comment why the data package may not be eligible for the accelerated approval pathway?
Yeah. When we received this comment in the file acceptance letter, and it was a preliminary conclusion of a potential review issue that we may not be eligible for review under the accelerated approval pathway, we requested a Type A meeting. FDA denied that request, saying that our review was ongoing, we were not stalled. But they did offer an informal clinical meeting to discuss the review pathway. They asked us to complete an assessment aid. So we put all of our clinical data and efficacy and safety data that had been in the BLA into the assessment aid template. We also completed some additional analyses that FDA had requested, then we submitted this assessment aid back in February.
Unfortunately, FDA took some time scheduling that clinical informal meeting, and it wasn't until we had new leadership in place at CBER and OTP that that meeting was scheduled in July. We held our clinical informal meeting in July. We presented the totality of our clinical data for efficacy and safety. We were also accompanied by representatives from the Patient Advocate Foundation, the Recurrent Respiratory Papillomatosis Foundation, as well as a KOL physician who treats a large number of patients. They both testified to the continuing unmet need and the meaningful clinical benefit that they see with INO-3107 and INO-3107's ability to meet that unmet need. We felt it was a very productive meeting. Unfortunately, FDA told us that due to the late stage of the review, they were unable to comment on the review pathway at that time.
Since then, we've completed all of our pre-licensure inspections, just had one observation, which we believe we have now resolved, and we're now expecting to enter labeling discussions in September.
Okay. Maybe you can remind us when the PDUFA is and if you have any outstanding thoughts going into that PDUFA date.
Yeah. Our PDUFA date is October 30th. As I mentioned, we're expecting to enter into labeling discussions, and we also will need to confirm the design of any confirmatory trial under the accelerated approval pathway with FDA.
Okay.
Will you be informing the investment community if you enter labeling discussions, or what are the next communicable milestones?
Yeah. Well, of course, we'll continue to keep everybody informed of any material information. But until FDA issue a final decision, I think it's important that we comment on sort of real facts as we go through these final stages of the review process.
How are you thinking about the design of a potential confirmatory study?
We had previously proposed to FDA a placebo-controlled design, so two to one randomization, active to placebo. It would be about 100 patients. We had alignment with FDA on that design ahead of submitting our BLA, and we're obviously waiting to have FDA's comments on that design. They did say at the late-cycle meeting that they will be providing us comments.
How does that satisfy full approval relative to what you are hoping to get under accelerated approval?
Yeah. So it is an interesting question. So our competitor was approved on a similar magnitude of data but from a single site. They received approval based on a reduction of surgery endpoint in year one and then duration data in year two. And we have provided data for both year one and year two demonstrating a reduction in surgery.
What else do you think you might need to do in a confirmatory trial?
I think the purpose of a confirmatory trial under accelerated approval is really to confirm the clinical benefit that you have shown. And I think a year one and a year two readout should do that.
Even though you've shown some of that data already
We believe that we've shown that already as part of our phase I/II trial, but FDA can always ask for additional patients, additional endpoints, et cetera.
Any sense of the size of a confirmatory trial?
We'd previously, based on our placebo-controlled design, we'd previously estimated about 100 patients.
So as you mentioned, there's a recently approved competitor product on the market. In the first quarter of this year, we saw around $22 million in sales, second quarter, $53 million. How do you interpret that sales trajectory in terms of the market opportunity and any sort of read-through for INO-3107's potential launch?
Yeah. So we think it's encouraging for us. I think it's a demonstration of the high unmet need and the pent-up demand out there. When we think about the numbers of potential RRP patients out there, we estimate, the epi data suggests that there are at least 14,000 patients based on some claims database work that we've done. We estimate it's significantly more than that. Based on our competitor's Quarter 2 data, they claim to have completed treatment of about 100 patients, another 100 patients enrolled. So by the time of our PDUFA date, they will still only basically have single-digit market penetration. So we believe the vast majority of the market will still be available to us. Of course, there are new patients being diagnosed every year, about 1.8 per 100,000. So those new patients will also be available to us.
I think also very importantly that, because the trials were done in different ways, our competitor enrolled patients who'd had three or more surgeries in the prior year. We enrolled patients who'd had two or more surgeries in the prior year. If payers are restricting reimbursement to clinical trial criteria, then we should have a slightly broader patient population that we can access.
How does INO-3107 differ from the competitor product, I guess mechanistically, and then in terms of the patient experience? How do you potentially see these two products coexisting on the market?
Yeah. Both products are generating T- cells against the virus, but they approach this in a very different way. With the competitor, they're doing the scoping and surgeries at doses three and four. We don't need to do that. They've previously published data that they're inhibited by the papilloma microenvironment. We've shown that we're not inhibited. Our efficacy isn't inhibited by the papilloma microenvironment. While both are generating T-cell approaches, we're generating T-cell approaches against different antigens and in a different way, and we think the quality of the immune response is really different. We think the surgeries that they're doing as part of the treatment regimen is another key differentiator. Over 80% of the patients in their trial required those surgeries. Over 40% of them required two surgeries. Again, that's another key differentiator. I think it's really important that the patients have options.
The existing product clearly doesn't work for all patients, and I think this is where INO-3107 can really step in and provide a solution for a broader population of patients. In the recently published guidelines from the RRPF Foundation, they indicated that should INO-3107 be approved, they would recommend it as first-line therapy.
Okay. Upcoming PDUFA date. Where do you stand on commercial readiness?
We're really ramping up our implementation plans now. We've made a lot of the key strategic decisions. We have our partners in place in terms of specialty distributor, specialty pharmacy, patient hub, 3PL, et cetera. We also announced at our recent earnings call that we'll be working with Syneos Health in terms of a contract sales organization, and we're also using Syneos Health in terms of MSL deployment. We're really excited about the upcoming PDUFA date and the opportunity to potentially commercialize INO-3107.
Okay. And then I guess in terms of RRP patients, where are they primarily located, and what sort of physicians are treating these patients?
Yeah. So it's really a small, concentrated market. RRP patients are treated by laryngologists, which is a subspecialty of ENT. We believe the majority of patients here in the U.S. are treated by 300- 400 laryngologists, and those laryngologists are based in about 100 treatment centers. So it's really a small, focused market, and we think we'll be able to address that with a relatively small field sales force.
Is there an ex-U.S. opportunity, and what would be your strategy for addressing that?
Yeah. Unfortunately, HPV is everywhere. So yes, there is a significant ex-U.S. opportunity, and we have interacted with the regulator, the European regulators, and the guidance we received from them was that we were likely to require a placebo-controlled trial in Europe for approval.
The trial that you're contemplating would satisfy EMA?
Potentially.
All right. I guess—
Pricing.
What did you?
Pricing.
How are you thinking about potential pricing?
The competitor product is priced at $115,000 per dose, so $460,000 for a full regimen. We will be talking about our pricing strategy a bit closer to launch, but clearly, we have been thinking carefully about our pricing.
Okay. I guess beyond INO-3107, what pipeline programs are you most excited about?
Yeah.
I know you have a lot going on.
We do have a lot going on. One of the big advantages of a platform like ours is you can address so many different diseases. We have really been trying to concentrate on the strengths of the platform, what can DNA medicines do better than other approaches. We have been focused on where T- cells, antigen-specific T- cells, are really important. Our lead clinical programs are really focused around HPV or cancer, where those T- cells are important. Following on behind INO-3107, we have INO-3112 addressing HPV 16 and HPV 18 positive head and neck cancer. We are partnered with Coherus there with their PD-1 that has been approved for nasopharyngeal carcinoma here in the U.S. Then we have a program in glioblastoma where we are partnered with Akeso with a bispecific CTLA-4 PD-1 inhibitor. Those are the next clinical programs.
At the moment, the vast majority of our resources are going into moving INO-3107 forward. We look forward to advancing those late-stage clinical programs when we have the resources. We also have some really exciting early-stage work where we're leveraging DNA medicine's ability to generate these proteins to go after diseases with missing or defective proteins, such as hemophilia A, Fabry disease, and hypophosphatasia. T- cell approaches and then protein replacement in the early stage.
Okay. Then I guess when the opportunity arises, how do you plan to prioritize these different late-stage pipeline programs?
Yep. It's going to be a tough challenge. We've been seeking partnerships for the early-stage programs. I think partnering is going to continue to be a key part of our strategy to enable to move these multiple candidates forward. We have a partner in China, for instance, ApolloBio, who are moving forward VGX-3100 and recently reported positive top-line data for HPV 16/ HPV 18 positive cervical dysplasia. I think partnerships are going to be key to us really exploiting the potential of the platform.
Okay. I know we only have a few minutes left, but perhaps you can remind us what investors should be watching for over the next 6- 12 months, and then perhaps over the next 18 months as well.
Yeah. I think from my perspective, clearly the PDUFA date is going to be pivotal for INOVIO. Then I think it's going to be us starting up the clinical trials for INO-3112, for INO-5401, and hopefully announcing some partnerships in the dPROT space. So that's our protein replacement disease pre-clinical programs.
Okay. Then maybe you can give us an update on the balance sheet and what your current cash runway is.
Yeah. So at the end of the second quarter, we had $36.7 million in cash. We then completed an offering that brought in another $18.3 million net. So our cash takes us into the end of the first quarter 2027, and through a potential launch of INO-3107 if approved.
Okay. I think that's all the questions that we have today. Jacky, thank you so much for joining us, and thank you everybody for attending this fireside chat.
Thank you very much.
Thanks.