...and thank you for everyone joining us this evening. With me today are Dr. Helen Sabzevari, President and CEO of Precigen, Harry Thomasian, our CFO, Dr. Clint Allen, Senior Investigator at the NCI, and Dr. Scott Norberg, Associate Research Physician at NCI. Before we begin, I would like to briefly review our forward-looking statement. During today's call, we will make various forward-looking statements. Investors are cautioned that our forward-looking statements are based on current expectations and are subject to risks and uncertainties that could cause actual results or safe harbor statements to differ materially. Please read our statement contained in this presentation, as well as risk factors contained in Precigen's most recent SEC filings, for a more complete discussion of these risks and uncertainties. On today's call, we will begin with Dr. Sabzevari giving us a brief look at our AdenoVerse gene therapy platform.
Following that, Dr. Clint Allen and Dr. Scott Norberg will go over the results for the pivotal study that were presented this morning at an oral presentation at ASCO. And then Dr. Sabzevari and our CFO, Harry, will go through the opportunity for PRGN-2012 in the platform, followed by Q&A with the team. With that, I would like to now turn the call over to Dr. Helen Sabzevari. Helen?
Thank you, Steve. First of all, I want to thank you, all of you, for joining us at the heels of this major milestone for RRP patients, for Precigen, especially today after the presentation of our pivotal data for PRGN-2012 in RRP by Dr. Norberg. An excellent presentation that it became very clear the medical community is really looking forward for this treatment for these patients, and this was quite clear today at ASCO. So I would like, first of all, to thank both Dr. Norberg and Dr. Allen for leading this trial for PRGN-2012. Also, I'd like to thank Precigen team, obviously, for all their efforts over the years to get this treatment to the patients.
Finally, our patients for participating, and we are thrilled with the results that we are seeing for our patients for the first time, for the treatment of this disease that has not had any treatment available for this patient population. With that, I would like to take a few minutes before I hand over the call to Dr. Allen, to go through our AdenoVerse platform. Why I'm doing that is very simple, because this platform of AdenoVerse that we have used for treatment for PRGN-2012 in RRP patients is quite differentiated from all the other AdenoVerse platforms. In a number of ways, and when you're looking at this slide, first of all, the large capacity of these vectors, these are gorilla vectors, that they have up to 12 KB.
So you can imagine the number of genes and epitopes that can be positioned in these vectors. Also, similarly, we have done a study in healthy volunteers, that in thousands of healthy volunteers, both in the United States, in Africa, that there is very little pre-immunity or no pre-immunity, meaning no neutralizing antibodies to these vectors. This is very important when it comes to repeat dosings of these vectors. Also, we have shown both in the studies of PRGN-2012 in clinic and also our PRGN-2009 in head and neck and cervical cancer patients, HPV-related cancers, that you can repeat those with these vectors continuously and enhance the immune responses, specifically T cell responses. This is quite unique to the gorilla, which even other vectors, such as chimp vectors, have not been able to accomplish that.
Also, as we are seeing as part of our pivotal data today, and we have demonstrated that in our PRGN-2009 in HPV-related cancer, that you get a specific responses, immune responses by T cells. In regard to the PRGN-2012, obviously, you will see some of the data that Dr. Allen and Dr. Norberg will show. Finally, we have a very highly productive manufacturing process for production of these Gorilla AdenoVerse vectors, which, as you can imagine, it becomes very important in commercial manufacturing of this. We are not only thrilled about the data that was presented and really excited for our patients and for the what we can now offer for this treatment. Also, I think this not only validates the PRGN-2012, but as a platform, it shows the capability of the Gorilla AdenoVerse platform that can be used in multiple indications.
As you might be aware, in our portfolio, we have PRGN-2009 addressing both head and neck cancer patients as well as cervical cancer patient. So with that, I would like to really hand over the call to Dr. Allen and Dr. Norberg, that will take us through the pivotal data that was presented today at ASCO, and it was received incredibly well. It was presented by Dr. Norberg and was received by medical community really outstandingly, and we are thrilled about that. So with that, Dr. Allen, I hand this over to you.
Yeah. Thanks, Dr. Sabzevari. Nice to meet all of you, at least on the call. I'm Dr. Allen. I'm a senior investigator in the NCI in the Intramural Research Program. So let's jump right in just so I can introduce you to the disease for those that aren't familiar, and then we'll go through the results just so we can get to the Q&A, because I'm sure you guys have questions. So let's go to slide 6. So, you know, recurrent respiratory papillomatosis, we'll call it RRP just for ease.
This is a disease where, for reasons we don't understand fully, people with otherwise completely normal immune systems will get a chronic HPV infection with type either 6 or 11, and these HPV types tend to cause infection in the mucosa of the throat and the voice box and the windpipe, and sometimes the lungs. And the manifestation of that infection is that you get these, you know, neoplastic papillomatous growths that grow in those areas, and because of the anatomically sensitive regions where these papillomas grow, if they grow on the vocal cords, they'll really destroy people's voice. I mean, this is a really devastating disease where, you know, people have these papillomas growths on their vocal cords. They're unable to speak, they can't hold down a job, their family and life with friends suffer. It's really devastating.
When the papillomas get big enough, they can cause airway obstruction, and in some patients, the papillomas kind of progress down into the lung parenchyma, and this can be fatal because of recurrent post-obstructive pneumonias. You know, the real devastating part about this disease is that it's recurrent, it's relenting, and it up to now, the only treatment that's accepted widely is recurrent surgery. So, surgery where you go either, typically, historically, you've gone under complete anesthesia. The surgeon goes in with tools through the mouth and basically tries to pull out or debride enough of the papilloma to maintain a patent airway and to try to debulk some of the papilloma on the cords.
You know, it's not unusual for some of these patients to have required hundreds of lifetime surgeries in order just to maintain a patent airway and a usable voice. You know, when you have that many surgeries, not only is the repeat anesthesia a risk, but you get this irreversible scarring, and sometimes kind of the results of the treatment can be just as bad as the disease. So there's been a real unmet need for a long time. In the world of otolaryngology, I think if you asked 10 otolaryngologists, "What's a bad problem in our field that we don't have an answer for?" They would say RRP, because these surgeries are difficult, the patients are devastated, and until now, there's really been nothing we can do. Slide 7, please.
The way this works, right, is that you have this adenoviral vector that has a DNA payload that encodes antigenic portions of HPV 6 and 11. You know, with a shot, this vaccine gets delivered. That virus does its job, and its job is to deliver that DNA payload to antigen-presenting cells and also provide probably some type I interferon signals to activate that innate immune response. Those antigen-presenting cells going on to step 3, then cross-present and prime and expand T cells in the periphery to develop a robust HPV-specific immune response. Then, critically, those T cells need to traffic from the periphery into the papilloma, or in the case of cancer, they traffic into the cancer. That's really what this is designed to do.
You know, we had completed a phase I study a couple of years ago, and that's all published. It's a Science Translational Medicine paper, and if you haven't read that, I encourage you to look at it. But based simply on these phase I results, we were granted Breakthrough Therapy Designation by the FDA, and we had already had Orphan Drug Designation by the FDA and subsequently received it for the European Commission. So that was really nice, obviously, because it gave us a pathway of interacting with the FDA that was a little bit different. And so those phase I results were, of course, very promising.
With what we showed in that study clinically was that the 12 patients that received what ended up being dose level 2, which is the higher dose of 5 times 10 to the 11th particle units, that half the patients had a complete response, and we'll kind of we'll go over what that complete response definition is. So let's go to slide 8 and then quickly slide into, slide number 9, and let's just get right into the pivotal study. So, the pivotal study, of course, was agreed to, in our conversations with the FDA, that it would represent, you know, the potential registration trial. And it was really just an extension of exactly what we had done in the phase I. So these patients are referred, to us at the NIH.
In this case, patients required 3 or more interventions in the 1 year prior to enrolling on the study to be eligible. I would take the patients to the OR as the surgeon and do a standard of care cleanout, and I would remove as much papilloma as I could safely, and later that same day, they get the first dose. So this is the boost or the initial vaccination, if you will. This is the prime. 2 weeks later, on day 15, they get the second shot, which we consider to be the first boost. Then on day 43, we scope them in clinic, and if they already have papilloma starting to come back, we take them back to the OR, and we clean that up. We clean up that minimal residual disease.
This is not a clinically indicated standard of care surgery. These are not people whose papilloma has already come back to where it was pre-treatment. This is our attempt throughout the treatment period to maintain minimal residual disease. If they don't have any visible papilloma at day 43, they don't go to the OR, and they just get the third shot either way. It's the same thing at day 85. That entire treatment period is over four months. During that four months, they get the four shots. They get one clinically indicated procedure, you know, which they need at the start of the study. Then at that six-week and 12-week mark, if they have any visible papilloma, we take them to the OR, and we clean that up.
I just want to make sure, make sure everyone on the call is clear that, you know, we actually scientifically feel that this approach, this design, is really critical. Maintaining minimal residual disease throughout the treatment period is the only treatment design for this disease that makes sense to me, and that's why we did it this way. The way I explain it to patients is, you know, whatever immune boost your body is going to get, that HPV-specific immune response has a better chance of fighting and eliminating a little bit of papilloma and a little bit of HPV, as opposed to a lot.
I think this disease, because of the way we treat it and because of how frequently these patients have procedures anyway, this is a really fantastic opportunity to take advantage of this principle of maintaining minimal residual disease, and it's the only design that made sense to us. So we then follow patients for 12 months after they've had the trial treatment. The way that we judge clinically whether this treatment worked for someone is we compare the number of patients... I'm sorry, the number of clinically indicated interventions that an individual patient required in the 1 year after the clinical trial, compared to the number of interventions that same patient required in the 1 year before. In this way, each patient serves as their own control. This is really important because there's a lot of variability between patients, right?
One patient might require 3 surgeries per year before the trial, some patients might require 8 or even 10, and it's very hard to compare between those patients, but each patient has consistency. So the only trial design that made sense to us was to use each patient as their own control and let each patient's immune response and outcome, you know, dictate whether or not they're a responder or not. Because of that variability that exists between patients, you know, for example, one patient might require 3 surgeries per, you know, in a given year, and the next year require 4 or maybe 2 surgeries in that year. To adjust for that little bit of variability, we decided to set a very high bar for considering patients' response. We only consider a patient an actual responder if they were a complete response.
In other words, if they did not require any clinically indicated procedures in the one year after the clinical trial compared to before. This is a, this disease is not a cancer, and this is an immunotherapy. We said, "If this is going to work really well, we want to set a really high bar to justify, you know, basically studying an immunotherapy in these specific patients." So that's the primary outcome measure of the pivotal study, is rate of patients that experienced a complete response. Let's go on to slide number 10. So in terms of patient demographics, this was very characteristic of, you know, adult patients with RRP, a fairly equal split of male and female. We had some juvenile-onset cases. What that means is this was RRP that was diagnosed at age 13 or younger.
Adult onset just means it was diagnosed at age 14 or older. You can see here the, you know, mean number of years that patients have had this disease. The mean number of surgeries for patients coming into this clinical trial was 4.5. So on average, patients were requiring, were requiring, you know, 4 or 5 surgeries in the year before the trial. And that's not very fun, right? I mean, that's not great for patients. That's a lot of procedures. The Derkay score is, is an objective measure that we, the physicians, calculate based on examination of patients that gives a, an assessment of disease burden. So the higher the Derkay score, the more papillomas, and the larger they are for an individual patient.
VHI-10 is a patient-reported outcome tool that allows patients to assess subjectively how they feel about their voice. And so the lower the number, the more patients feel like that their voice is usable and not disordered. The higher the number, patients feel like their voice is very disordered. Let's go on to slide 11. So of course, we had established what we feel like is a really outstanding safety profile from the phase one, but absolutely with the phase II, we wanted to make sure that that was still true. So in the 35 total patients treated, and what we're considering to be kind of the combination phase one-two study, these are all patients that received that dose level 2 of 5 × 10 to the 11th particle units.
We really see very, very mild side effects, no grade three or four treatment-related adverse events. The way that we prep patients for this is we say, particularly after the first shot, "You're probably going to feel like after you've how you feel after you have a flu shot or maybe a COVID shot." So these, you know, patients experience self-limiting, you know, low-grade fever, body aches, chills, typically for 24 hours or less. We don't give patients opioid pain medications. We say, if you feel like it, take a Tylenol and you're going to be fine. So really, an outstanding safety profile. Slide 12. So the primary outcome measure of this registration, pivotal registration study was rate of patients that experienced a Complete Response.
Again, these are patients that had some number of procedures clinically indicated and required in the year before, and after the four PRGN-2012 treatments in the study period, required no intervention in the year after. Overall, out of those 35 patients, we had 18 of them experience a complete response, so a complete response rate of 51% overall. This number was really consistent between the 12 patients in the phase I and the 23 patients in the phase II, which is nice to see. Overall, over 85% of all the patients that enrolled in the study required fewer, numerically fewer interventions, clinically indicated interventions in the year after the trial compared to before. Let's go on to Slide 13. This is looking at the data a different way with a little bit more information.
So the way to read this swimmer's plot is that that vertical black line right in the middle, that's the study period, that's the treatment. The bars that are gray and the associated numbers to the left of that vertical black line are the number of clinically indicated procedures that each individual patient, each represented by a row, required in the one year before the study. And you can see some of those numbers are 8 and 10. I mean, these are people that are going to the OR or having a procedure almost every month to maintain their airway or the voice. I mean, it's a horrible disease. The numbers and the bars to the right of that vertical black line are the number of clinically indicated procedures that each patient required in the year after.
You can see about the top half of this swimmer's plot, all those numbers to the right are zero. Those are the complete responders. The number of clinically indicated interventions required in the year after for the non-complete responders are in the blue bars below. It's an impressive swimmer's plot. Slide 14, please. So, you know, really important to us was understanding, were we getting a magnitude of immune response sufficient to give durable disease control? I mean, comparing 1 year after to 1 year before the trial is great, but what we really want is to have durable benefit for these patients.
So what you're looking at here is a swimmer's plot, where each row is an individual patient, and on the Y-axis, you see the number of months since completing the study treatment for each of those patients, and the length of the lane of the swimmer's plot is the durability of response. So however long that green bar is, that is the length of time after completing the clinical trial, that the patients still have not required a clinically indicated procedures. Almost all of these durable responses are ongoing, and the median duration of complete response has not been reached. It should be noted that the blue bar on the left-hand side, those numbers are the number of clinically indicated interventions that each of those patients required in the one year before.
Clear evidence of durable response in the patients that are complete responses, which is really nice to see. Slide 15. Here you have a few representative images. These are four patients, patients 5, 7, 11, and 13 from the study. On the left-hand side is the pretreatment image. You can see various degrees of bulky papillomatous disease on the vocal cords or above the vocal cords. And on the right-hand side are the post-treatment images, and inset in each of those images is the number of months after completion of treatment that that image was taken. So really clean, clear mucosa, not only complete response in the sense that they haven't required procedures, but literally no visible disease, which is incredible.
I say it's incredible because we've tried lots of other treatments for this disease, including immune checkpoint blockade, and we've never seen anything like this. That's incredible. On the right-hand side, you've got some quantification of improvement in Derkay score, which is, again, an objective measure of the amount of bulk of disease, and on the bottom, improvements in that subjective patient reporting tool of voice quality. This is 24 weeks after completion of trial treatment compared to pretreatment, just some numerical quantification of these improvements. Let's go to slide 16, please. A lot of work was done in the initial 15 phase I patients that we treated to really understand how we were activating immune response and what some of the differences were between responders and non-responders.
And I'm happy to get into some of that data in the question and answer if it comes up. But again, all that's published in the Science Translational Medicine paper. But we felt like it was really important also in these phase II studies, to validate the mechanism of the vaccine and assess whether or not we could experimentally measure whether the vaccine was doing what it's supposed to do, right? And as a peripherally administered vaccine, the vaccine is supposed to enhance, either induce or expand existing HPV-specific immune responses in the blood. And these are the results that you're looking at here on this slide. So the Y-axis here is the basically magnitude of interferon gamma response represented as fold change over baseline.
So if, you know, the number is above that 2 that you see, the horizontal dotted line, that means that there was at least a twofold greater interferon gamma measurement of HPV-specific immune response after the clinical trial compared to before. Each dot represents a pool of HPV-specific antigens that was used to stimulate peripheral blood T cells. And what I would encourage you to take away from this plot is that there are positive, you know, greater than two full changes in both the responders and the non-responders. We do see a greater magnitude of more HPV-specific responses in the patients that were in this plot, defined as responders, which were all the clinical—all the complete responses, and all patients that had a greater than at least 50% reduction in surgeries post-treatment compared to pre.
But, you know, we also see positive induction of HPV-specific T cell responses in the blood and the non-responders as well. And this really gets to this concept that we think we're demonstrating here, which is the vaccine does what it's supposed to do in everybody, right? The vaccine works. The difference really seems to lie in some of the features of the papilloma and how these newly induced or expanded HPV-specific T cells from the blood traffic into the papilloma and are allowed to do its, do their job. And again, I would refer people back to the Science Translational Medicine paper because we tease out a lot of those mechanisms. Slide 17, please. So to conclude, the results of the pivotal registration study, we have a complete response rate of 51%, 18 out of 35 patients. We couldn't be happier about that number.
86% of patients had a decrease in the number of interventions after the clinical trial compared to before. We feel like this is really safe, with only mild, mostly grade one, a few grade two adverse events. No grade three, no grade four adverse events. We didn't talk a lot about the anti-drug antibody response, but what I will say is, and again, this is published in the Science Translational Medicine paper for the first 15 patients. What we observe is that we do not see sequential additive increases in antibody titers with subsequent doses. In other words, the overall neutralizing antibodies that tend to form the actual titer quantities are low. But importantly, even more importantly than that, is, you know, you don't see it go up with the third dose and the fourth dose, and I think that's a really important feature.
I think we're clearly demonstrating that this vaccine has the ability to elicit HPV-specific T cell responses, and that this is resulting in clinical benefit in most patients, greater than 50% of patients. Again, this is a pivotal study, and so this was all discussed and agreed to with the FDA at a time, and we're really excited about where this is going in the future. So I think, I'm going to stop there, and with slide 18, we'll turn it back over to Dr. Sabzevari.
Thank you so much, Dr. Allen. As I mentioned, obviously everyone can understand the enthusiasm and, excitement that we have here at Precigen, and we are very grateful to our investigators, for the accomplishment for our patients here. What I would like to do in the next two slides is just to address, obviously, where we are with the program. As we have mentioned in this next slide, you see that where our PRGN-2012 is on track for potential commercial path. As, Dr. Allen mentioned, obviously, we have received the accelerated path from FDA, and, as we have communicated before, we anticipate to submit, our rolling BLA by the end of second half of this year, and, we are preparing for the commercialization in 2025.
As we have done all of preparation and we are finishing that for commercial launch in 2025, including all the necessary market research analysis, of course, the medical affairs teams that are in place, in engaging with KOLs and patient supporting groups, and the market access and distribution groups, and involvement with the payers engagement and specialty, establishing a specialty distribution. So as we mentioned, now on the heels of this pivotal, excellent pivotal data, that we are moving to our next position for preparation for commercialization in 2025.
I would like to finish the basically presentation by pointing out that our PRGN-2012 and in this, gorilla adenovirus platform, really has the potential to be the first and the best in the class for RRP treatment, based on what was mentioned, not only clinically, but also we have seen both from clinical side, the efficacy that Dr. Allen and Dr. Norberg have presented, as well as the very favorable safety. But at the same token, the ease of the subcutaneous administration of the drug, as Dr. Allen mentioned, this is like a injection of the flu vaccine. Basically, you receive it subcutaneously without requirement of anything else or any other device. We also have established a mechanism of action for a strong HPV 6 and 11 specific T cell responses, and we have shown that this can be given number of times....
Because of the differentiation of the gorilla adenovirus compared to other adenoviruses and viral vectors. We have received the orphan drug designation, both from FDA and EMA, the breakthrough therapy designation from the FDA, and, as I mentioned, the rolling BLA submission, we are anticipating in the second half of this year. So based on that, we are thrilled, and at this point, I will hand it back over to Steven, and we can prepare for our Q&A.
Thank you, Helen, and thank you, Dr. Allen, for this presentation. I'll turn the call back to the operator now, so she can assemble the queue for questions, and we look forward to talking further. Thank you. Operator?
Thank you. We will now be conducting a question-and-answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we pull for questions. Thank you. Our first question comes from the line of Ben Burnett with Stifel. Please proceed with your question.
Hey, thank you, and congrats on these data. It's, it's great to see so much consistency with the phase II and the phase I, coming in like that. I wanted to ask just like one clarification question. Yeah, I think it was mentioned just in terms of the protocol, that when... so it's a 4-dose course, but when patients are assessed for the third and fourth dose, there's a potential for additional cleanout. I was just curious, what proportion of patients, was that necessary for?
Yeah, good question. So in general, patients that were complete responders only required the initial clinically indicated surgery and required either neither the 6- and 12-week or required maybe the 6-week, that in general, that's true. And in general, the patients that are gonna be non-responders, clearly had papilloma, you know, growing back, but at that 6- and 12-week mark. So all the details of who required the 6- and 12-week minimal residual disease trim up, for the phase I patients, that's all detailed in that Science Translational Medicine paper. And of course, we'll formalize all that data in publication form for the phase II, but in general, that's the trend.
Okay, super helpful. And I guess just also for the company, just wanted to see if you maybe just talk about kind of the commercial strategy, the key touchpoints. And then, I guess, do you have a sense, you know, for the size and scope of sort of the commercial footprint that you'd be targeting?
So, thank you, Ben, for asking. So in regards to the commercialization, obviously in the U.S. for 2025, as you know, we have our own on-site commercial manufacturing facility that is being prepared. And, we based on, as I mentioned, the high productivity of the cell lines that we have for our gorilla adenovirus cell lines, we anticipate that we can easily provide the doses that are required for thousands of patients, as we move into 2025, and this is already in preparation. So we anticipate that we have the necessary, basically drug available for the treatment of the patient, both for U.S. and, also ex-U.S.
Okay. That's great. Thanks so much, and congrats again.
Thanks, Ben.
Thank you. Our next question comes from the line of Jennifer Kim with Cantor Fitzgerald. Please proceed with your question.
Hi, thank you for taking my question, and congrats on the data. Maybe a first question for Dr. Allen. Thank you for the presentation. I'm just wondering, as you look at the totality of the data, how would you incorporate this treatment into your practice? And specifically, would the location of the papillomas matter for treatment decision? And would number of prior surgeries matter in terms of who you would like to treat? That's the first question.
Yeah, good, good question. So we do not see an association between either the total number of lifetime surgeries or the number of surgeries required in the year before the treatment. We do not see a clear association between that and treatment response, so I would not use that as a variable. We also do not see a clear association between where the disease is located and, you know, chance of having a complete response, so I wouldn't use that either. And if I take my investigator hat off and put my practicing Johns Hopkins otolaryngologist hat on, I would give it to everybody. You know, the drugs are gonna have a label, and of course, I and everyone else would always recommend following that label.
The reality is, you know, as soon as a patient has a diagnosis of RRP, when this is on the market, I think people are gonna give it right away.
Okay, that's helpful. Thank you. And then a second question, maybe for the team and Helen. How does the phase II data feed into your confidence heading into accelerated approval filing? But also as you move the confirmatory study forward, and I think you said filing might come toward the end of this year. Is there any color in terms of timing of the confirmatory trial initiation? Thanks.
Yeah. So absolutely. First of all, in regard to the consistency of our phase two data, as you can see, and Dr. Allen and Dr. Norberg today presented at ASCO, this is really unprecedented, right? When you look at the phase one and you see 50% response and then the phase two in 23 patients, now you see 52%. I always—when I look at this data, say, even in a preclinical model, it's very, very unusual to come this close. So definitely, this gives a tremendous level of confidence, and I think it's extremely important also for these two similar trials serving as a pivotal and especially with the designation that FDA has given us. So that is quite obviously important, and we are thrilled about that.
I do apologize, Jennifer, what was the second part of the question?
Oh, I think you said during your prepared remarks that filing could come toward the end of this year, and I'm wondering, do you have any color on the timing of initiating the-
Yes.
confirmatory trial?
Yeah. So for a rolling BLA, we said that we will be our rolling BLAs on track for submission for the second half of this year, and we anticipate for the commercialization by 2025. As far as a confirmatory trial is concerned, it's ongoing, and I think one of the things that has been very important for us, we already have a confirmatory trial design, a single arm, very similar to the pivotal design that was just presented. It was very important that we are going to initiate these confirmatory trials, obviously, prior to the full submission of the BLA.
All right. That's helpful. Thanks, guys, and congrats.
Thank you. Thanks, Jennifer.
Thank you. As a reminder, press star one to ask a question at this time. Our next question comes from the line of Jason Butler with Citizens JMP. Please proceed with your question.
Hi. Thanks for taking the questions, and let me add my congratulations on the results. First one, just in terms of the T cell responders. I understand, Dr. Allen, that you broke out responders versus non-responders. I was wondering if you could comment on whether there was differences in T cell responses between partial responders and non-responders, i.e., those patients that didn't have any change in surgeries in the 12 months after. And then secondly, just maybe for the company, thoughts about the market here. The trial looked at patients needing at least 3 surgeries in the prior 12 months. What proportion of the patient population do you think that represents?
Is the confirmatory study also looking at that same population with, you know, 3 or more surgeries in the prior 12 months? Thanks.
Yeah. So I'll... Thanks for your questions, Dr. Allen. So I'll answer the T cell part. So yeah, we see almost like a continuous variable gradient. So we observe greater magnitude HPV-specific T cell responses in the blood of patients that are complete responses, responses. And we see less than the complete response, but more than the non-response, you know, HPV-specific T cell responses in the partial responders. And again, I think it's important to highlight just one more time that we still see induction of HPV-specific T cell responses in the non-responders.
You know, all of the scientific data we have to date really points to that it's a, it's a problem with T cell trafficking, with these, you know, important T cell chemokines, CXCL9, 10, 11, as it relates to some HPV driven pathology in these non-responders. So, thanks for that good question.
Sorry, just to jump in there, Dr. Allen, can I follow up? So, so how do you think about the potential for retreatment, you know, after 12 months or some period of time in, in those partial responders?
Sure. Yeah, I think it's a very reasonable question, and, I'm going to give you a very boring answer, which is we should we should absolutely study it clinically, in a trial. But, you know, until we have that trial and we have the clinical data, I would say, you know, I don't really know. But from a scientific standpoint, there's absolutely no reason why we couldn't and why we couldn't have the hypothesis that it's entirely possible that retreatment could further boost, you know, that HPV-specific T cell response. We just got to do the study.
Okay. Hi, Jason. This is Helen. And, in regard to the second part of your question and the confirmatory trial and the number of the patients with the three and more, obviously, we assume that at least around 33%, between 25%-33% of the patients, RRP patients will fall in the category of three and more. However, as Dr. Allen mentioned, and I think we believe, we believe that when there is this the treatment that can be so efficacious in patient population that are also severe, this can be applied to a less severe patient population. So we're definitely looking forward in regard to that. And in the confirmatory trial, as we have mentioned, specifically, we have had already the discussions with the FDA.
We are very excited that our design has been accepted and very similar to the pivotal that we have done.
... Okay, great. Thanks for taking the question.
Thank you, Jason.
Thank you. Our next question comes from the line of RK with H.C. Wainwright. Please proceed with your question.
Thank you. Thanks for taking my question, and congratulations, Allen and team. So, just trying to understand, within these patients, what's the history in terms of Gardasil coming into the trial? And also, does Gardasil ever help any of these patients once diagnosed?
Yeah, great. Great question. So, almost all of these patients, I don't have an exact number for you, but I can tell you it is almost all of them, probably 90% or greater, have already received Gardasil from their either home family physician or their home ENT after they were diagnosed with RRP. The reason for that is, that it's safe, and everyone should get vaccinated with Gardasil because, you know, obviously the 9-valent covers a lot of different types, and even if you're not gonna get clinical benefit, clinical treatment benefit from a preventative vaccine when you already have, you know, an HPV 6 or 11 infection established, you get protection against, you know, all the others.
So anytime anyone asks me, "I got a patient with XYZ disease, should I give Gardasil?" Before they even finish the word Gardasil, I say, "Yes, like, everyone should get it." Mechanistically, there is no scientific rationale that inducing a strong humoral, you know, immune response, where you get high antibody titers, does anything to an established HPV infection, where the virus is already inside the cells. Like, the immune system just doesn't work like that. There is retrospective data in the literature from, you know, you know, retrospective, highly biased and, you know, people meaning well, but very, you know, uncontrolled studies.
And looking at in basically case series, you know, a single institution, you know, will retrospectively go back and look at their 10 RRP patients and see how many of them got Gardasil and see if there's, you know, a difference in the number of procedures after the clinical trial compared to before. And about half the case series you look at suggest there is a small clinical benefit and about half don't. And I think that, you know, the reason is why there's just not a great scientific rationale for why that would work.
So whenever we talk about the vaccine, either at a conference or whatever, I mean, we always draw a clear distinction between a preventative vaccine that gives you a strong antibody response to prevent an infection like Gardasil versus a therapeutic vaccine designed to activate a strong T cell response, which the T cell is the only immune cell in our body that can detect and kill a cell already infected with the virus. So thanks for that question.
Thank you. Thank you, thank you. Really helpful. And then, you know, a couple of times, you have stated that, even though you see T cells in the non-responders, you are thinking that it's possibly the trafficking ability is what is making them not to respond. Are there any other ways to increase that, the trafficking in such that you get the T cells to the right place?
Yeah, great, great question, and definitely the ongoing topic of both, you know, preclinical and hopefully planned clinical studies. You know, exactly, exactly addressing that question, you know, if we think we understand what the problem is, is there something safe, you know, that we can do maybe even to the papilloma directly to kind of, you know, change this chemokine profile to get better recruitment of these newly activated T cells? Absolutely, a point of ongoing study, and I'd love to have a much more definitive and attractive answer for you in the future on that.
Thank you very much. Really appreciate, you taking both my questions. Thank you.
Thank you, RK.
Thank you. Our next question comes from the line of Brian Cheng with J.P. Morgan. Please proceed with your question.
Hi, thanks for taking our question. This is Sean on for Brian. Could you tell us, maybe elaborate on how the patient characteristics in the pivotal phase two compare to the real-world distribution of severity in RRP? And also, how should we really think about the commercial adoption curves if this gets approved?
Yeah. So I, you know, I think our patient characteristics are very characteristics of adult adults with RRP. We didn't see anything, you know, that was skewed in terms of, you know, gender or, you know, number of required procedures, either total lifetime or in the year before. I mean, as I said, it's, you know, very, very, very typical for patients to have required, you know, at least dozens, if not hundreds of lifetime surgeries. So I think, I think, you know, every trial obviously has clear inclusion criteria, and I think our inclusion criteria of requiring three or more interventions was just a number we had to decide. And we decided that number because, of course, you know, in a clinical trial, we want to make sure we're getting the, you know, patients that have high burden of disease, right?
That, you know, as Dr. Sabzevari said, maybe capture, you know, the top quarter to one-third of all RRP patients. We wouldn't want to make, you know, the inclusion criteria too loose and show great efficacy in people with really mild disease and then, you know, not have it work for patients with worse disease. So the best answer I can give you is, I think our trial population in totality of the 38 patients is very representative of adult patients across the U.S. that have RRP.
Thank you, Dr. Allen.
Thank you. Maybe-
Yeah. Yeah, in regards to the commercial question that you had, as we have communicated-
Yeah.
Obviously, based on our research market research analysis, we have shown that there are at least 15,000-20,000 cases of RRP in the United States and perhaps more than 125,000 cases in ex-US. So clearly, this speaks to the commercial viability, and from the perspective of treatment and for the PRGN-2012. And clearly, as Dr. Allen mentioned, and I also previously sort of emphasized it, obviously, we have gone to the more severe patient population because I think Dr. Allen said it just perfectly. If it works in a more severe population, then you can definitely translate back that to the much patient population that they have a easier disease, whereas the other way around usually is not necessarily the fact.
Therefore, we are very confident, and we are really excited about the data that has been shown and the ability to be useful for all patients in the treatment of RRP.
Yeah. And just one quick follow-up to that because I think it's an important point to talk about. That, you know, we really view, and here I'm wearing, I guess, more of my, my, federal employee, NCI investigator hat. You know, we, we review, kind of, look at this. The results of this trial really being a big step forward for the concept of using therapeutic vaccination to treat, diseases caused by chronic infection, where you have no antigen. And so, you know, there's a lot of diseases caused by chronic infection with viruses. There's a lot of other diseases caused by chronic infection with HPV 6 and 11, including, you know, anogenital condyloma, which affects millions of people per year.
So, you know, we're very interested in promoting and doing whatever we can to study the safety and efficacy of this, even this exact vaccine and other disease states, that are really problematic for people worldwide and people in underserved communities.
Got it. Thank you for the clarity.
Thank you.
Thanks, John.
Our next question comes from the line of Ben Burnett with Stifel. Please proceed with your question.
Hey, thank you for letting me ask a follow-up question here. I just wanted to follow up on this discussion around the T-cell responses that you're seeing, Dr. Allen, either in this study or with your experience in the phase I population. I'm just curious if you're seeing similar T-cell responses to HPV 11 versus 6, or is one kind of more prominent than the other?
Dr. Norberg, I think, Dr. Allen, do you want to take that question?
Yeah, what we can say is that we've seen responses to both HPV-6 viral antigens and also HPV-11 viral antigens in patients. So we can say that, you know, what we found is that it can elicit a response against viral antigens from both the different types.
Fantastic. And are these the two antigens that are the two HPV strains and antigens that are associated with anogenital condyloma?
Yes.
Okay. Okay, thank you.
That is one of the reasons that genital warts, I think, another indication that gene therapy vaccines such as PRGN-2012 can be very beneficial for these patients because it's the exact same infection of HPV 6 and 11, as you can imagine. And in that sense, millions of patients in the United States and in ex-US that are suffering from that.
That's very interesting. Okay, thank you so much for the clarity.
Thanks, Ben.
Thank you. There are no further questions at this time. I would like to turn the floor back over to management for closing comments.
Thank you, Alicia, and thank you for the presenters and the questions. I'd like to pass the call over to Harry Thomasian for some concluding remarks, and then I'll turn it back to Helen for final remarks.
Thanks, Steve. I just want to touch on the company's finances, but before I do that, I want to reiterate what Helen had said earlier. You know, today is a significant day in the life of Precigen, and we are really excited about the PRGN-2012 data that was shared with the public today. We've been laser-focused on shoring up our balance sheet and have fielded a number of inbound inquiries in support of our efforts to commercialize PRGN-2012. We're considering all strategic options. Our ultimate goal at Precigen is, and always has been- developing critical therapies for patients while maximizing value for our shareholders. I am confident that we will continue to meet that goal. With that, I'm going to turn that back over to Helen.
Thank you very much, Harry. Again, I'm gonna echo what we have said at the beginning. Today is really a milestone for myself as a drug developer in my life. When I look back, how many times you come back to the point that you have drugs at hand, that is gonna change the life of, if not hundreds of thousands of patients, but millions? I think this is one of those pivotal moments for the field, for Precigen, and I cannot be more grateful to our investigators, Dr. Allen, Dr. Norberg. I think I wish all of you could be there at ASCO this morning for the incredible presentation and the way that it was received. Then also, I wanna thank our patients for really this journey and bringing this treatment to them.
And finally, the Precigen team, that they have been working tirelessly in the past years to bring this treatment forward. And finally, I'm gonna echo what Harry mentioned. I think we are very excited about our data. We are extremely excited about the path forward. And also we have, as Harry mentioned, we have received inbound inquiries that we are strategically, we are in the position to strategically evaluate it, and we will be in touch further with as weeks comes up. And so with that, I thank you, all of you, for joining us, and I thank everyone here. So thank you.
This concludes today's teleconference. You may disconnect your lines at this time.