Precigen, Inc. (PGEN) Earnings Call Transcript & Summary

Good evening, and welcome to the Precigen PRGN-2012 Pivotal Study Results and Update Call. [Operator Instructions] Please note, this event is being recorded. I would now like to turn the conference over to Steve Harasym, Vice President of Investor Relations. Please go ahead.

Thank you, Alicia, 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 Position at MCI. Before we begin, I would like to briefly review our forward-looking statements. 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. And 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 to this patient population. So 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. And 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 platform. In 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 1000s of healthy volunteers, both in the United States and Africa, that there is very little pre-immunity or no pre-immunity, meaning no neutralizing antibodies to this vector. And this is very important when it comes to repeat doses of these vectors. Also, we have shown both in the study of PRGN-2012 in clinic and also on 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. And this is quite unique to the Gorilla, which even other vectors such as the chimp vectors have not been able to accomplish that. Also, as we are seeing in part of our pivotal data today, as we have demonstrated that in our PRGN-2009 in HPV-related cancer that you get a specific response of 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. And finally, we have a very highly productive manufacturing process for production of this 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 it's really excited for our patients and for the -- what we can now offer for this treatment. But also, I think this not only validate the PRGN-2012, but as a platform, it shows the capability of the Gorilla AdenoVerse platform that can be used in multiple indications. And as you might be aware, in our portfolio, we have PRGN-2009 addressing both head and neck cancer patient as well cervical cancer patients. 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 it over to you.

Yes. Thanks, Dr. Sabzevari. Nice to meet all of you, at least on the call. I'm Dr. Allen, I'm one of the senior investigator in the NCI and the Intramural Research Program. And 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 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 to the voice box and the wind pipe and sometimes the lungs. And the manifestation of that infection is that you get these neoplastic papillomatosis growth that grow in those areas and because of the anatomically sensitive regions, where these papillomatosis grow, they grow on the vocal cords, they'll really destroy people's voice. I mean this is a really devastating disease where people have these papillomatosis growths on their vocal cords, they're unable to speak, they can't hold down a job, their family and life of friends suffer, it's really devastating. When the papillomas get big enough, they can cause airway obstruction and in some patients, the papillomas almost kind of progress down into the lung, parenchyma and this can be fatal because of recurrent post obstructive pneumonias. And 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 cords. And 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. And when you have that many surgeries, not only is the repeat anesthesia risk, but you get this irreversible scarring and sometimes the kind of the results of the treatment can be just as bad as the disease. And so -- there's has been a real unmet need for a long time. And in the world of Otolaryngology, I think if you asked to an otolaryngologist, 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. So the way this works right is that you have this adenoviral vector that has a DNA payload that encodes antigenic portions of HPV6 and 11, and 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 1 interferon signals to activate that innate immune response, those antigen presenting cells going on to step 3, then cross-presenting prime and expand T cells in the periphery to develop a robust HPV-specific immune response. And then critically, those T cells need to traffic from the periphery into the papilloma or in the case of cancer they need to traffic into the cancer. And so that's really what this is designed to do, and we completed a Phase I study a couple of years ago, and that's all published at the 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 x 10 to 11 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 #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 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 three 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 to do a standard of care cleanout. And I would remove as much Papilloma as I could safely and that -- 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. And 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 pretreatment. 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. And it's the same thing at day 85. So that entire treatment period is over 4 months. During that 4 months, they get the four shots, they get one clinically indicated procedure, which they need at the start of the study. And then at that 6-week and 12-week mark, if they have any visible papilloma, we take them to the OR, and we clean that up. And I just want to make sure everyone on the call is clear that we actually scientifically feel that this approach, this design is really critical. Maintaining minimal residual disease throughout the treatment period is the only treatment designed 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 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. And 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. And so we then follow patients for 12 months after they've had the trial treatment. And 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 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. So in this way, each patient serves as their own control. And this is really important because there's a lot of variability between patients, right? One patient might require three surgeries per year before the trial, some patients might require eight 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 dictate whether or not they're a responder or not. The way -- because of that variability that exists between patients, for example, one patient might require three surgeries per -- in a given year. And the next year require four or maybe two surgeries in that year. And 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 1 year after the clinical trial compared to before. This is a -- this disease is not a cancer, and this is an immunotherapy. And we said, if this is going to work really well, we want to set a really high bar to justify -- basically studying an immunotherapy in these specific patients. And 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 #10. So in terms of patient demographics, this is very characteristic of 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 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 requiring -- we're requiring four or five 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 an objective measure that we, the physicians calculate based on examination of patients that gives 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 I. But absolutely with the Phase II, we want 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 I/II study, these are all patients that receive that dose level 2 of 5x10 to the 11th particle units. We really see very, very mild side effects, no grade 3 or 4 treatment-related adverse events. The way that we prep patients for this as we say, particularly after the first shot, you're probably going to feel like after you -- how you feel after you have a flu shot or maybe a COVID shot. So, these patients experience, self-limiting, 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 [indiscernible] on, 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 4 PRGN-2012 treatments in the study period required no intervention in the year after. And overall, out of those 35 patients, we had 18 of them experienced a complete response, so a complete response rate of 51% overall. And this number was really consistent between the 12 patients in the Phase I of 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 swimmers plot is that, that vertical black line right in the middle, that's the study period, that's the treatment. The bar and the numbers that are -- 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 1 year before the study. And you can see some of those numbers are 8 and 10. I mean these are -- 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 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. So you can see about the top half of the swimmers plot, all those numbers to the right are 0. Those are the complete responders. And 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 swimmers plot. Slide 14, please. So really important to us was understanding where we're 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 swimmers 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 swimmers 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 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 1 year before. So 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 pre-treatment image. You can see various degrees of bulky papillomatosis 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 image 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. And 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 pre-treatment, just some numerical quantification of these improvements. Let's go to Slide 16, please. So 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 kind of 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 full change over baseline. So if the number is above that 2, that you see the horizontal dotted line, that means that there was at least a two-fold 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 greater than two-fold 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 complete responses and all patients that had a greater than -- at least 50% reduction in surgeries post-treatment compared to pre. But 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 allowed to 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 could 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 1, a few Grade 2 adverse events, no Grade 3, no grade 4 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 tighter quantities are low. But importantly, even more importantly than that is 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. 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 their accomplishments for our clinicians, yes. What I would like to do in the next 2 slides is just to address, obviously, where we are with the program. As we have mentioned in the next slide, you see that where our PRGN-2012 is on track for a 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. We have done all of the 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 market access and distribution groups and involvement with the payer's engagement and especially in establishing a specialty distribution. So as we mentioned, now in the heels of the pivotal -- excellent pivotal data that we are moving to our next position for preparation for commercialization in 2025. And I would like to finish the basically presentation by pointing out that our PRGN-2012 and in the gorilla AdenoVerse 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 sub-q administration of this drug. And Dr. Allen mentioned, this is like an injection of the flu vaccine, basically, you receive subcutaneously with our requirement of anything else or any other device. We also have established a mechanism of action for a strong HPV6 and 11 specific T cell responses. And we have shown that this can be given a number of times because of the differentiation of the Gorilla AdenoVerse compared to other Adeno vectors and viral vectors. We have received 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 QA.

Thank you, Helen, and thank you, Dr. Allen, for this presentation. I'll turn the call back to the operator now since she can assemble the queue for questions, and we look forward to talking further. Thank you. Operator?

[Operator Instructions] Our first question comes from the line of Ben Burnett with Stifel.

Congrats on these data. 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 one clarification question. 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?

Yes, good question. So in general, patients that were complete responders only required the initial clinically indicated surgery and required either neither the 6- and the 12-week or required maybe the 6-week in general, that's true. And in general, the patients that are going to be non-responders clearly had papilloma growing back at that 6- and 12-week mark. So all the details of who required the 6 and the 12-week minimal residual disease trim-up for the first -- 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, I just wanted to see if you can maybe just talk about kind of the commercial strategy, the key touch points. And then I guess do you have a sense 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 AdenoVerse cell line. We anticipate that we can easily provide the doses that are required for thousands of patients as we move in 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 the U.S. and also ex-U.S.

Our next question comes from the line of Jennifer Kim with Cantor Fitzgerald.

Congrats on the data. Maybe a first question for Dr. Allen. I'm just wondering, as you look at the totality of the data, how would you incorporate this treatment into your practice? And specifically, with the location of the papilloma's matter for treatment decision and would number of prior surgeries matter in terms of who you would like to treat? That's really the question.

Yes, 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 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 a 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 Hopkins, otolaryngologist hat on, I would give it to everybody. The drugs are going to have a label. And of course, I and everyone else would always recommend following that label, but the reality is, as soon as a patient has a diagnosis of RRP when this is on the market, I think people are going to give it right away.

Okay. That's helpful. 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?

Yes. So, first of all, in regard to the consistency of our Phase II data, as you can see and Dr. Allen and Dr. Norberg today presented at ASCO, this is really unprecedented, right? And when you look at the Phase I and you see 50% response and then a Phase II in 23 patients, now you see 52% I always -- when I look at this data, I say even in a pre-clinical 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 the two single arm trial 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. And in -- I do apologize Jennifer, what was the second part of the question?

I think you said during your prepared remarks that filing could come towards the end of this year. And I'm wondering, do you have any color on the timing of initiating the confirmatory trial?

Yes. So for rolling BLA, we said that we would be -- our rolling BLA is 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. No, it was very important that we are going to initiate these confirmatory trials, obviously, prior to the full submission of the BLA.

[Operator Instructions] Our next question comes from the line of Jason Butler with Citizens JMP.

Let me add my congratulations on the results. First one, just in terms of the T cell responders, I understand Dr. Allen, 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 with needing at least three surgeries in the prior 12 months, what proportion of the patient population do you think that represents? And is the confirmatory study also looking at that same population with three or more surgeries in the prior 12-months?

Yes. So I'll -- thanks for your questions. Dr. Allen here, I will answer the T cell part. So yes, 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. And we see less than the complete response, but more than the non-response, 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 and all of the scientific data we have to date really points to that it's a problem with T cell trafficking with these 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, just a follow-up. So how do you think about the potential for retreatment after 12-months or some period of time in those partial responders?

Sure. Yes. I think it's a very reasonable question, and my -- I'm going to give you a very boring answer, which is we should absolutely study it clinically in a trial. But until we have that trial and we have the clinical data, I would say 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 that HPV-specific T cell response. We just got to do the study.

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% to 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 that when there is this, the treatment that can be so efficacious in patient population that also severe, this can be applied to less severe patient population. So we're definitely looking forward in regard to that and in the confirmatory trials, as we have mentioned. Specifically, we have had already the discussions with FDA. And we're very excited that our design has been accepted and very similar to the pivotal that we have done.

Our next question comes from the line of RK with H.C. Wainwright.

Congratulations Helen and team. So just trying to understand in 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?

Yes. 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 obviously, the 9-valent covers a lot of different types. And even if you're not going to get clinical benefit, clinical treatment benefit from a preventative vaccine when you already have an HPV6 or 11 infection established, you get protection against all the others. So anytime anyone asked 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 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 -- retrospective highly biased and people meaning well but very uncontrolled studies. And looking at -- in basically case series, a single institution, will retrospectively go back and look at their 10 RRP patients and see how many of them got GARDASIL and see if there's a difference in the number of procedures after the clinical trial compared to before. And about half the case series, you look like suggest -- suggest there is a small clinical benefit and about half don't. And I think that 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.

Really helpful. And then a couple of times you have stated that even though you see T cells in the non-responders, you're thinking that it's positively, the trafficking ability is what is making them not to respond. Are there any other ways to increase that trafficking such that you get the T cells to the right place?

Yes. Great question. And definitely, the ongoing topic of both pre-clinical and hopefully planned clinical studies, exactly addressing that question. If we think we understand what the problem is -- is there something safe that we can do maybe even to the papilloma directly to kind of 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 and the future on that.

Our next question comes from the line of Brian Cheng with JPMorgan.

This is Shaun on for Brian. Could you tell us, maybe elaborate on how the patient characteristics in the pivotal Phase II compared to the real-world distribution of severity in RRP? And also, how should we really think about the commercial adoption curve if this gets approved?

Yes. So I think our patient characteristics are very characteristics of adults with RRP. We didn't see anything that was skewed in terms of gender or number of required procedures, either total lifetime or in the year before. I mean, as I said, it's very, very typical for patients to have required at least dozens, if not hundreds, of lifetime surgeries. So I think 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, in a clinical trial, we want to make sure we're getting no patients that have high burden of disease, right, that as Dr. Sabzevari said, maybe capture the top 1/4 to 1/3 of all RRP patients. We wouldn't want to make the inclusion criteria to loose and show great efficacy in people with really mild disease and then have -- not have it work for patients with disease. So the sense that 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.

Yes, in regards to the commercial question that you had, we have communicated, obviously, in -- based on our research -- market research analysis, we have shown that there were at least 15,000 to 20,000 cases of RRP in the United States and perhaps more than 125 [indiscernible] cases. In ex U.S., so clearly, this speaks to the commercial liability. 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 that Dr. Allen said it just perfectly. If it works in a more severe population, then you can definitely translate that to the much patient population that they have an easier disease whereas the other way around usually is not necessarily the fact. And 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.

And just one quick follow-up to that because I think it's an important point to talk about that we really view -- and here I'm worrying, I guess, more than my federal employee NCI investigator had, 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 there's a lot of diseases caused by chronic infection with viruses. There's a lot of other diseases caused by chronic infection with HPV6 and 11, including anogenital condyloma, which affects millions of people per year. So we're very interesting 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.

Our next question comes from the line of Ben Burnett with Stifel.

Let 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 HPV11 versus 6? Or is one kind of more prominent than the other?

What we can say is that we've seen responses to both HPV6 viral antigens and also HPV11 viral antigens in patients. So we can say that what we found is that it can elicit a response against viral antigens from both the different types.

Fantastic. Are these the two antigens that are the two HPV strange antigens that are associated with anal genital condyloma?

Yes.

That is one of the reason that genital warts, I think, as another indication that gene therapy vaccine such as PRGN-2012 can be very beneficial for these patients because it's the exact same infection of HPV6 and 11, as you can imagine. And in that sense, millions of patients in the United States and in ex U.S. that are suffering from that.

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 has said earlier. Today is a significant day in the life of Precigen and we are really excited about the PRGN-2012 data that we 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 of 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 want to turn that back over to Helen.

Thank you very much, Harry. And again, I'm going to 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 going to change the life of, if not hundreds of thousands of patients but million. And 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. And 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. And then also, I want to thank our patients for really this journey, and bringing this treatment down. And finally, the Precigen team that they have been working tirelessly in the past years to bring this treatment forward. And finally, I'm going to 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 a 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. Thank you for your participation.