All right, thank you again, everybody, for joining us here at the Citizens Life Sciences Conference. Next company we have is exciting: INOVIO Pharmaceuticals. I think they're still on track to have the first DNA immunotherapy approved in the U.S. You know, mRNA gets a lot of attention or has gotten a lot of attention, but there's some very differentiating aspects of DNA. I think most recently demonstrated with their DMAb, monoclonal antibody durability data that we'll hopefully get into. We're happy to have CEO Dr. Jacque Shea and Dr. Mike Sumner, Chief Medical Officer here, to present this story. Maybe Jacque and Mike start, just briefly review the platform, how it differs from these other platforms like mRNA or viral platforms, and maybe how broad you can go with DNA.
Yeah, great question, Morgan. Thanks very much for the invitation. Nice to be here today. When you think about DNA medicines and RNA medicines, they're both nucleotide-based therapies. There are actually quite a lot of differences between the two platforms. The mRNA molecules are inherently more unstable than DNA. DNA is much more stable. They're also delivered in different ways. mRNA requires lipid nanoparticles for delivery and to protect the mRNA from degradation. Whereas with DNA, we use our proprietary delivery systems called CELLECTRA. mRNA can be quite dependent on ultra cold chain for distribution. DNA being much more stable, we don't require any frozen shipping or storage. When you think about the kinds of immune responses that mRNA generates versus the DNA medicines platform, mRNA is very good at generating very high, ultra high levels of antibody, especially neutralizing antibody.
DNA is very good at generating T cell responses, particularly CD8 T cell responses. When you contrast the DNA platform with viral vectors, obviously with the DNA platform, we do not need to worry about any pre-existing anti-vector immunity or generating anti-vector immunity as part of repeated dosing. That is a key differentiator there. When you look across both mRNA platforms and viral vectors, another key difference with the DNA platform is that we do not have those kind of flu-like adverse events that you can get with the mRNA and with viral vector administration. Those are some of the key differences.
Okay, great. And you know, based on the data that I've seen, I'd put the difference in durability between DNA and mRNA, you know, a couple orders of magnitude, hundreds. Is that fair?
When you look at the durability of the protein expression, I mean, as we've recently shown with our most recent DMAb data, we can get much more sustained in vivo protein production of the different proteins that we're encoding with our DNA medicines. Whereas with mRNA, you're getting much more rapid turnover.
Right. Okay. It is not just a 10% difference or 50% difference, it is multiples. Just sticking to the platform, a couple more details. Do you know if lipids are used in the injection of the DNA? Is it just saline?
That's right. When we're administering our DNA medicines, it's literally just the DNA plasmids, which are circular molecules of DNA that we insert our optimized gene sequences into, and then some salts and water. No lipid nanoparticles associated.
Okay. And then how many patients total have, you know, received an injection? What's the safety and tolerability profile been so far?
Yeah, I'll let Mike talk about that, Mike.
We're now up to about 19,000 administrations in 6,000 subjects. We've actually been fortunate also to conduct some placebo-controlled studies with our platform. Really, we see beyond some mild tolerability associated with the administration, we really do not see any differentiation between the placebo-reported adverse events.
Okay, great. Just a couple more platform, and then we'll get into 3107. What are the general COGS for the manufacturing cost, maybe excluding the device? And then the device can be used multiple times, right? If you had a flu clinic and you were doing flu vaccinations, they could use it all season and multiple seasons, correct?
Yeah. So let's talk about, first of all, let's talk about the drug components. So our DNA medicines platform, we have commercial scale manufacturing for our plasmids conducted at various CMOs. We're manufacturing lots in the tens of thousands of doses. It really depends on the scale of manufacturing as to what the costs of goods are. If we're going for a vaccine indication, clearly we need to get the cost of goods down much lower than we would for a therapeutic indication. Cost of goods is really dependent on the scale of manufacture. When it comes to the device, we have a suite of different devices. For our lead program, 3107 for recurrent respiratory papillomatosis, we're using our IM delivery device where we're delivering the plasmids usually to the deltoid muscle.
For vaccine indications where we're looking to generate more of an antibody response as opposed to a T cell response, we tend to use intradermal delivery. Both devices are able to be used, both our IM devices and our intradermal devices are able to be used multiple times. We use single-use disposables, which are the patient contacting piece, and you're just changing that out with each administration.
Okay, great. All right, let's get into INO-3107. You mentioned it. You said the full name, so say it once, don't need to say it again. RRP is the indication. Maybe, Jacque and Mike, if you could discuss the RRP, what is the indication, what causes it, the unmet need, prevalence in the U.S.?
Great. Maybe I'll kick off there. RRP is a rare disease of the respiratory tract. It's caused by HPV-6 and 11, and it generates these kinds of wart-like growths or papillomas, primarily in the larynx and the vocal cord. The way the sort of disease manifests is this affects patients' ability to talk. It can affect breathing. In some cases, you get dissemination of the RRP lesions down into the lungs as well. That, unfortunately, has a low rate of malignant transformation and can be pretty fatal. Patients who are undergoing treatment for RRP, the standard of care is repeated surgery. An RRP patient's life is really problematic. You're constantly wondering when these lesions are going to come back. You're having to undergo surgery to remove them and then go on to voice rest. You're going into repeated cycles of this.
Every surgery for an RRP patient comes with both risk and cost. There is the risk of permanent damage to the vocal cords. By the time you have had 10 or more surgeries, 80%-90% of patients have had some form of permanent damage to their vocal cords. Obviously, there is the cost in terms of quality of life, economic costs, et cetera. It is a really difficult disease for patients to deal with.
Okay. I think the data that we've seen on the prevalence suggests about 14,000 active patients. That data is a little bit old. Do you expect that number is higher, lower now? Has Gardasil had any real impact? Do you expect it to have impact going forward or is that kind of stabilized?
Yeah. So the 14,000 came from a survey that was done quite a while ago. It is relatively old data, and we think it's probably an underestimate of the incidence of RRP within the population. In terms of HPV vaccination, what we're actually seeing here in the U.S. is levels of HPV vaccination holding pretty steady, certainly not increasing currently. And the majority of adults in the U.S. are still unvaccinated. So unfortunately, what that means for RRP, according to HPV experts, is in the adult population, we're not going to see a decrease in RRP cases for at least a generation to come. When you look at some other HPV-related diseases, such as HPV-related throat cancer, the incidence there is actually going up. Currently about 20,000 new cases of HPV- 16 and 18 related throat cancer are diagnosed each year in the U.S. expected to go up to 30,000 cases by the end of the decade. Unfortunately, RRP is going to be with us for a long time to come.
Okay. You guys are almost ready to submit the BLA. I think, are you still on target to have that potentially accepted by year end? I guess what's gating for that? Can you request, you're going to request a rolling review. Can you request that now or do you need to wait for these stability studies?
Mike?
Yeah. What we guided on our last call was that we will target commencing rolling submission in the middle of this year. The reason we are waiting till then is obviously we are currently completing a design verification testing for the device. When you are dealing with the FDA, they appreciate a very defined timetable so that they can schedule their resources for the review. As soon as we are certain of the timing of the testing, we will request rolling review. All the non-device modules are ready to be filed. We are targeting to get the file accepted by the end of the year, which would give us a PDUFA date, hopefully in the mid-year next year with priority review.
Okay, great. Maybe you can discuss the prior, you know, you had a prior timeline delayed a little bit due to this manufacturing issue. Maybe just discuss what the issue is, what you need to do to address it, and kind of where you are in that process.
Yeah. Last year, we identified a manufacturing issue with a single-use disposable array component of our device. That required us to go back. The issue was in relation to an injection molded plastic component of that array. We had to go back and basically strengthen that plastic component within the array. We had to conduct testing to show that that fix was appropriate and resolved the problem. We announced in our last earnings call in March that we believe we've resolved that issue. We're now completing the combination testing of the array and the device together, which is the data we'll need to submit as part of our BLA submission.
Okay, great. That is a third party doing that testing, right?
Yes, it's a third party doing that BLA testing also, although some of the testing is performed in-house.
Okay. All right. Maybe let's talk a bit about the, so you have a phase I, two that's been completed, open label. What did that trial show you and how did it inform the confirmatory study that you need to do? Maybe let's get into the, at some point, the confirmatory trial design too.
Mike?
Okay. Yes, we have a phase I/II study. We recruited 32 patients across eight U.S. sites. They actually had a median of four surgeries in the preceding 52 years coming into the study with a rate.
Sorry?
52 weeks.
52 weeks. Sorry. Coming into the study. And so with a range of two to eight. Significant burden of illness coming into the study. We then gave four doses over a nine-week period. We count every single surgery from day zero against efficacy, because as you heard from Jacque, every single surgery is a meaningful event to these patients. What we saw was a statistically significant reduction from a median of four down to a median of one. 72 % of those patients actually saw a 50% or greater reduction in the number of surgeries that they had.
Okay. Great. You did not mandate a surgery before the first dose of 3107, is that correct?
They had a clinically warranted surgery. It was part of the normal disease management of these patients. That was counted in the preceding 52-week period.
Right. Okay. Got it. Okay. Understood. Maybe discuss, before we get into the confirmatory trial and what you're thinking there, you have a pretty differentiated design. The durability, you recently showed some durability out through, I think it was up to three years. Maybe discuss that. Kind of maybe surprisingly, the data actually looked to get better. Maybe just tell us what that showed.
Yeah, absolutely. We were able to go back and look at, get data on 28 out of the original 32 patients. As you said, we now have data out to a median of 2.8 years in that patient population. What we saw was continued clinical improvement. I think that links to the fact, as Jacque talked about, we get that protein, continued protein secretion. We have a very robust immune response that we documented at the 52-week period. It is not really surprising that these patients continue to improve. What we saw was that the patient numbers that saw a 50% or greater improvement now increased up to 86% from 72%. 50% of those patients required zero surgeries in that year two period.
Okay, great. Yeah. So complete response rate went from 28% to 50%, correct?
Okay. I think there were four patients lost to follow-up. Why were those patients lost?
Two were not back in contact with their physicians, which, as you can imagine, in a rare disease, that hopefully means that they're doing well and they didn't want to come back. Two patients did not want to consent into the study.
Okay. Okay, great. Do we have enough natural history data out there? Was this a pretty representative population going into the trial? What are you planning maybe to discuss the confirmatory trial? You and Precigen both need to start the confirmatory trial before submitting the BLA, correct? Maybe discuss your trial design and how it's a bit different.
Yeah. So just answering your first part, we actually have previous data on the patients into our trial from three years. We are now actually able to look at that three-year period and compare it to the 2.8 years of data. In our year two, we're seeing a 75% reduction in the number of surgeries. However we look at the data, we're seeing a significant impact on the disease. When we started discussing our confirmatory study with the FDA, they really gave us two options. They said, if you want to mirror the population that we had in the original study, i.e., two or more surgeries, then you need to run a placebo-controlled study. It is clearly a benefit to us to have a broader population as we look to bring this product to the market.
We were in discussions with the European regulators, and they were very clear that we needed to bring to them placebo-controlled data to get approval in the future.
Just to add to that, when we looked at the patients we enrolled in our phase I/II study, we had patients who'd had between two and eight surgeries in the prior year with a median of four surgeries. That seems to align very well with the disease severity that you see across RRP. Also, very importantly, we had a mix of both HPV-6 patients and HPV-11 patients, even a couple who were co-infected with both HPV-6 and HPV-11. Gender balance, again, very similar to the population, which you see with RRP, which tends to skew male. We believe our phase I/II population was very representative. We conducted that phase I/II study across eight clinical sites. Again, a good different representation of the different standards of care.
Okay. Do you plan to use those same sites for the confirmatory trial?
You also, sorry, I forgot. You also asked about our plans. We actually plan to expand our clinical trial site base. We're actually looking at 20+ U.S. sites. Over half of those are already under contract and several have IRB approval. When we're in discussions with the FDA, I mean, the goal of them saying start a confirmatory study is really to demonstrate to them that we can meet the commitment of delivering the data that they need for confirming our efficacy in a timely manner. I think we have a very robust plan and actions to demonstrate that we will do that.
Okay, great. How is the, in the trials, how do you make the determination to do a surgery? Is that the investigator? Is there any kind of central review for this? Is it going to be the same for both trials of phase I/II and the confirmatory?
We obviously did document the evidence behind why surgery occurred in our phase I/II . They were all linked with growth of papilloma. Taking that data, we've obviously refined how we're going to record the need for surgery. There is always a personal element between the surgeon and the patient. It can be dependent on where that papilloma grows. I mean, for me, if I had RRP and I had a single papilloma on my vocal cords that was impacting my voice, I would want that operated on. If I was somebody who was at the end stage of my RRP and I already had that permanent vocal cord damage, your sensitivity around the impact on your voice is going to be less. It really has to be patient and surgeon specific at the time based on the symptoms that patient is having.
Okay, great. Yeah. I think the placebo-controlled bit didn't mention it earlier. It's great with the new administration and their commentary. Have you had any interactions with the new people at FDA, if any are dealing with you? Any changes in your interactions?
Yeah. Our interactions with the FDA have been pretty similar. We're not seeing any changes currently.
Okay. You know, way back in the program, it basically sounded like FDA told you to file this on the data that you have, right? This was kind of surprisingly to me, I guess, I don't know what the right word is, not lenient, but accommodating from the agency.
We were very excited with our phase I /II data. In discussions with the agency, they gave us breakthrough therapy designation. They called us up, as you said, and said, actually, we think this data is good enough to file under the accelerated approval program. We have been working closely with the agency since then, and we are very excited about this path.
Okay, great. I have more questions, but maybe people have to, we're running out of time, get to them in one-on-ones. I want to talk a bit about the DMAbs. I thought that data was pretty amazing, actually. Recently had a publication for some COVID antibodies that have already actually been used in their antibody form. Maybe just discuss that platform, what you can do and what the data showed us.
Yeah. This is some of our really exciting next generation DNA medicine technology. What we were doing in this proof of concept trial was we were expressing two different monoclonal antibodies against COVID-19 within the same patients. We were demonstrating, we were following production of those monoclonal antibodies in the circulation, showing that they were functional and showing that we were not generating any anti-drug antibodies. We were able to show sustained levels of production of the monoclonals and presence in the circulation out to 72 weeks. We saw a dose respondent level of production as well. We did not see evidence of any anti-drug antibodies in more than 1,000 blood samples across the participants. Very excited by that proof of concept technology.
Clearly, what it means is we can apply that technology to other monoclonal antibodies, but we can also apply the technology to protein replacement diseases. Because at the end of the day, what we're doing is producing proteins within the body. They can be therapeutic proteins such as monoclonal antibodies, or they can be other kinds of proteins, for instance, to address protein replacement diseases. We are very excited by the prospects of that technology and what it could mean for patients.
What do you expect to advance next out of the DMAb or protein replacement programs?
Yep. We have a number of different candidates in development. We also are talking with some potential partners. Clearly, we'll look to move those on as best we can. However, the vast majority of our resources are clearly focused on getting INO-3107 across the finish line. That is really where our focus is at the moment.
Yeah, makes sense. Okay. Maybe discuss quickly INO-3112 for oropharyngeal cancer partnered with Coherus BioSciences. Yeah, just what's next for that program? Where is that at?
Yeah. We have been in discussions with both the FDA and European regulators. We are aligned on the patient population that we are going to be studying, which is patients with local, regionally HPV-driven 16, 18 throat cancer. We are focusing on the high-risk population. These are the patients that the surgeons look at them and they say that they know they are going to relapse. It is just a question of when. That is based on their tumor size, the nodal involvement, their extensive smoking history. What we are going to look to do with the combination of 3112 and the anti-PD-1 LOQTORZI is to try and prevent that relapse in those patients. Because once they do relapse, they have very poor outcomes with sort of overall survival of around 12 months.
Okay. About how many patients is that in the U.S.? When do you think you might start the phase III?
I've talked to the patient side. I mean, HPV-driven throat cancer is now the most frequently diagnosed HPV-driven cancer. They're estimating 30,000 patients by the end of 2029. We're estimating that high-risk population is currently somewhere around 3,000-4,000 patients.
Each year.
Each year.
Okay. Okay.
In terms of when we start the study, as I said, we're putting most of our resources into getting 3107 across the finish line. Clearly, once we've accomplished that, then we'll start moving the rest of the pipeline on.
Okay. Last question, the cash position and your runway.
Yep. At the end of the year, we had $94.1 million in cash. That cash runway takes us into the first quarter of 2026.
Okay, great. Okay. Thank you, Jacque. Thank you, Mike. Appreciate it.
Thank you.