Precigen, Inc. (PGEN) Earnings Call Transcript

Hello, and welcome to the Precigen Virtual R&D Day for PRGN 2012. At this time all participants are in listen-only mode [Operator Instructions] As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Steve Harasym. Please go ahead.

Thank you, Kevin, and thank you to all joining us for this update call today. Before we begin, I'd remind everyone that today's call 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 outcomes to differ from those indicated by our forward-looking statements. Please read the safe harbor statements contained in this presentation as well as the risk factors contained in Precigen's most recent SEC filings for a more complete discussion on these risks and uncertainties. Today, I am pleased to be joined by Dr. Helen Sabzevari, President and CEO of Precigen; and Dr. Clint Allen, Senior Investigator, Surgical Oncology Program Center for Cancer Research and NCI and lead investigator for the PRGN-2012 clinical trial. Following our prepared remarks, we will open the call to Q&A. In addition to audio questions, we invite our listeners to submit questions through the conference portal, and we will get to these time permitting. I will now turn the call over to Dr. Allen for some background on RRP.

Well, thanks, and good afternoon, everyone. So I'm Clint, Dr. Allen. I'm at the NCI. I'm a fellowship-trained laryngologist, a board-certified otolaryngologist and I've been taking care of folks who have our RRP or Recurrent Respiratory Papillomatosis for a long time. So as a way of background, RRP as we'll refer to it, is caused by a chronic infection with either HPV Type 6 or 11 human papillomavirus. These two are distinct subtypes from HPV 16 or 18, which caused cancer, HPV 6 or 11 cause RRP. And essentially, infection of the throat, voice box and tracheal linings will lead to the development of papillomas. So the pictures you see on the left-hand side, this is a normal shot on top of a voice box. Those are the vocal cords, those two white strips, and below that as a normal trachea with nice smooth mucosa. On the right-hand side, you can see a severe case of RRP where papillomas growths have developed really across all mucosal surfaces. So because of the location of these papillomas, patients will experience extreme voice disturbance. The vocal chords essentially cannot close and vibrate, which is our sound production mechanism for speaking. If the papillomas become large enough, as you see in this photo on the right, both on top and bottom, these can eventually obstruct the airway. So this is a really devastating disease that can start when you're a child, in which case we call it juvenile onset, it can start when you're an adult. I have treated patients that had onset of RRP that first showed up in their 80s, 80 years of age. And our real problem with RRP is there is no approved systemic treatment to address the underlying problem. And we often tell patients that papilloma is not your problem, the problem is that for reasons that are incompletely understood, your immune system is allowing a chronic infection with HPV 6 or 11. And the papillomas are just a manifestation of the disease. And the real heart of the issue is trying to get the immune system to clear the HPV, which in case will clear the papillomas. So the only treatment that we really have for this right now is repeat surgery to debulk the papillomas and maintain an open airway both for voice and breathing. And it is not unusual for individual patients to have hundreds of lifetime procedures, including many of those being surgeries in the OR sometimes being awake laser procedures in the office just to maintain a safe airway in the service of voice so they can work and have a family life and carry on with some quality of life. So if the heart of the issue to treat RRP in the future is going to be to activate the immune system to clear that underlying HPV 6 or 11 infection, which is the real cause of the problem. The question is, how do we do that? And here at the NIH, we've actually done many clinical trials already using many forms of immunotherapy to try to activate those HPV-specific T cells. It's important here to start to distinguish what's the difference between a therapeutic vaccine such as PRGN-2012 or a preventative vaccine like GARDASIL. So GARDASIL is a preventative vaccine activates the immune system against HPV in a way that you get production of antibodies, and it prevents you from getting an infection. And we know that, that's very effective. In general, people who are vaccinated with GARDASIL as a preventative vaccine at a young age, they will not develop RRP or other HPV-related disorders. The problem is, once you already have the infection and the virus is already inside the cells, getting a preventative vaccine like GARDASIL that produces antibodies doesn't really do you any good. The only immune cell in the body that can detect and kill a cell such as epithelial cell lining your throat or voice box infected with HPV is a T cell. Specifically therapeutic vaccines are designed to activate the immune system in a different way that specifically leads to activation of T cell-based HPV specific responses. In our previous immunotherapy clinical trials that were using primarily immune checkpoint blockade for RRP, these are all published. We learned that patients with RRP tended to not have strong or activated but suppressed HPV-specific T cells in their papilloma. So when we gave other forms of immunotherapy, there weren't good T cells to unleash. This really led us to change our strategy and come up with the idea that we needed to really develop a therapeutic vaccine to induce new or expand existing HPV-specific T cells. I think this is really the key moving forward for RRP to address the underlying problem, which is the infection. Again, papillomas are not the problem. Papillomas are what caused the symptoms lead to the frequent surgery, lead to the devastating side effects. It's the underlying HPV infection that's the problem, and treatment strategies moving forward need to be aimed at addressing that underlying issue.

Thank you, Dr. Allen, and thank you for this thorough background on this terrible condition. I'd now like to turn the call over to Dr. Helen Sabzevari, who will now take us through the background on the PRGN-2012 AdenoVerse Immunotherapy.

Thank you, Steve. As Dr. Allen has mentioned, I think it has become clear that what we need to do for this patient population is really to invoke their immune system and generate high specific T cells to HPV 6 and 11 epitopes that stops this chronic infection. While using our AdenoVerse platform, which is a library of gorilla vectors that are well-differentiated from others. We thought that we can bring a drug products for this patient population that might be changing the paradigm here. I should say a little bit about our Gorilla Adenoviral vectors. When I say they are differentiated, first of all, from a perspective of the 0 positivity, when you look at the healthy volunteers, and we have done this both in the United States and across in other continents, you can see that volunteers usually, we do not have either 0 posivity or pre immunity to these vectors or if there is it's very slight. Unlike other viruses such as Ad5 or retroviruses, lentiviruses and other families of these viruses. Why is that important? The importance here is if you don't have 0 positivity, you can do a repeated dosing of these vaccines. And in this clinical trial as well as in other clinical trials that we have used a similar backbone of viruses for cancer, also, we have shown that you can prime and boost number of times over a period of time, and we have had patients that they have been over a year, 1.5 years vaccinated in our oncology trial. And you can continuously enhance the immune responses, specifically the T cell responses. As far as the neutralizing antibodies are concerned, they stay -- they come up and they stay at bay. And you do not keep increasing this neutralizing antibody. This is one of the major differentiation factor of this platform. Another part here that is important is really the capacity of these adenoviral vectors that they have a much larger capacity than, for instance, Ad5 that is below 5 kb. And here, you have up to 12 kb. Why is that important? You can put a much more comprehensive epitope designs in there or number of genes that it can go in there and present it to the immune system. On the right-hand side, I just mentioned that what you are looking at the graph, the bar graph, this is PBMC from the RRP patient population that Dr. Allen mentioned, they don't have really a specific T cell responses. And this is after being exposed to PRGN-2012. Now you can see clearly that you are inducing a specific T cell responses to HPV 6 and 11 epitopes. In the next few minutes, what I'd like to share with you is a video of the mechanism of action of our Gorilla Adenovirus platform. And specifically in regards to the PRGN-2012 and showing you that actually by design the epitopes that are specific to HPV 6 and 11 within these vectors, you can directly induce T cell is specific to HPV 6 and 11 in patients directly that they have a high affinity that they can basically recognize the infected papilloma and affected cells and destroy them. So let's look at the video together here. [Presentation]

Thank you to Dr. Sabzevari. I'm now going to turn the call back to Dr. Allen, who's going to walk us through the data for this trial.

So let's talk about our completed Phase I clinical study. So this is a first-in-human study to evaluate the safety and efficacy of PRGN-2012. So we opened this up for adult RRP patients who had what we categorize as severe RRP. In other words, they require three or more interventions in the 1 year prior to enrollment. This likely captures 25% to 30% of the most severe RRP. We brought them in. We did a standard-of-care surgical cleanout that administered four doses of subcutaneous. It's a subcutaneous injection, PRGN-2012 over a 3-month period, 85-day period. We exposed patients to 2 dose levels, 3 patients got dose level 1, which is onetime [ 1011 ] viral particles then after demonstrating safety, an additional 12 patients received dose level 2, which was 5 times [ 1011 ] viral particles. So our primary outcome measure for the study is safety, of course. In terms of efficacy, the way we assessed whether patients benefited clinically was comparing the number of clinically indicated interventions that they required in the 1 year after completing the clinical trial compared to that same patient's need for clinically indicated interventions in the 1 year before the clinical trial. The patients were referred to the NIH for the clinical trial. And after the clinical trial, the patients were referred back to the same physician, the same otolaryngology surgeon that they had prior to the clinical trial to remove as much bias as possible. So the patient and the physician making clinically indicated decisions about what was needed after the clinical trial was exactly the same as that partnership before the clinical trial. We have several objective and subjective measures of response, namely the Derkay score and the Voice Handicap Index. We'll go after that -- we'll go over that in the coming slides. So as I said, we enrolled 15 patients. These were all adult onset. We had 10 male, 5 female. 2 of our patients had juvenile onset. In other words, they developed RRP initially when they were children or adolescents and that RRP disease severity maintained into adulthood. The remainder of the patients did not develop RRP until they were adults. This is a patient population. These 15 patients have very severe disease. These patients had an average of over 6 surgeries in the year prior to the clinical trial. And I cannot underline enough how devastating this is for patients. The surgeries and the interventions that these patients require to have 6 or more of them in a year. These are often general anesthesia procedures where they're asleep for sometimes multiple hours depending on the severity of the disease. It's a huge stress around the body. And for most people undergoing 6 or more interventions in a year for any indication will be devastating, but especially for an indication that involves your airway, which leads to very high-risk surgeries, complications can be very, very severe. Let's go next. So a summary of treatment of emergent adverse events can be summarized by saying that this drug is extremely well-tolerated. Almost all patients develop what we would characterize as an injection site reaction. Again, this is a subcutaneous injection. And what most people get as something very analogous to the flu vaccine and we often tell people that they're going to have side effects that's probably better than what they experienced after the COVID shot. So people typically get about 1 day or often less of injection site redness, a little bit of swelling, a little bit of tenderness. It's almost all grade 1 occasional grade 2 and never limits their activity in any way. Patients also give what we would characterize as like a viral prodrome, typically for 1 to 2 days, low-grade fever, chills, some fatigue, every once in a while, we'll have someone where it last 2 days. It's always self-limiting. We don't give them medicine or anything like that, very well tolerated. Again, all grade 1 grade 2 adverse events, no Grade 3, no grade 4, certainly no dose-limiting toxicity. Next slide. Here's a more complete summary of these. We'll let you peruse these. I won't go through them in detail. But again, very, very common occurs in almost all patients. In fact, we tell patients to expect it. We say, listen, especially after this first shot, you're going to have 1 to 2 days of injection site soreness. You're going to feel like you're coming down with a cold, and it's going to go away. We've very rarely see it go beyond 2 days, very well-tolerated. Let's look at some initial efficacy data. So what you're looking at here is what we call the swimmers plot. So on the Y axis, you see patient number 1, 2 and 3, these are the 3 patients that received dose level 1, that lower dose of the vaccine, again 4 shots after a standard-of-care cleanout. Everything you see to the left of that middle 0 line indicates the number of clinically indicated interventions that each patient required in the year before. And to the right and the green bars, these are the number of clinically indicated interventions, the patients acquired in the 12 months after the clinical trial. So you can see even with dose level 1, the lower dose, we see a substantial reduction for several of the patients and the number of clinically indicated interventions in the year after. A different way of looking at the same data is to ask the question, well, after the clinical trial, how long did it take for the patient to require another clinically indicated intervention indicative of disease recurrence? And you can compare that to the surgery interval in the 12 months before. And for these 3 patients, what we see is a mean surgery interval of 55 days and a post treatment interval or basically time to recurrence of 180 days. Every surgery matters in these patients. And if you ask me what a significant reduction in the number of clinically indicated interventions is, the answer is any. So to have any patient go from 8 surgeries a year and only require 3 in the year after that is profoundly significant for that patient. Next slide. What you're looking at here is a very similar swimmer plot data, but for dose level 2. Again, on the left-hand side, patients 4 through 15, again, each received that higher dose of the vaccine, 4 shots in the adjuvant setting. On the left-hand side in the gray bars, there's a number of clinically indicated interventions in the year before the clinical trial to the right blue pot -- the blue bars we see are the indicated interventions in the year after. So you might notice some zeros and that's a big deal. So patients 5, 7, 10, 11, 13 and 14 in total, half, 50%, 6 out of 12 dose level 2 patients had what we are classifying as a complete response. In other words, these are patients that had sometimes a significant number of interventions in the year before that required no interventions in the year after. We've been doing clinical trials for years at the NIH. And we've never seen any data, any close to this in terms of complete response. If we consider a partial response as patients that required 50% or fewer interventions in the year after. In total, we have 7 out of 12 at dose level 2 that obtained what we would call an objective response. And 10 out of 12 patients required fewer interventions in the year after. So any reduction in the year after. We had 2 patients that were true nonresponders that require the same number of interventions in the year after compared to the year before. Again, a different way of looking at the same data is to ask how long did it take for the patient to require a surgery after the clinical trial and then to compare that to the inter surgery interval in the 1 year before. In patients 5, 7, 10, 11, 13 and 14 on the top of the swimmer plot, no surgery has been required. So this data has just cut off at our last assessment of that patient and the remaining patients there's been some extension of the inter surgery interval. But again, this just highlights in those 6 patients on top the complete responses with no interventions requirements. So in summary, at dose level 1, which is the lower dose level, we had 03 patients experiencing a complete response, but all patients required fewer interventions in the year after compared to the year before. And 1 patient was officially categorized as a partial response with a greater than 50% reduction in the need for surgery. And dose level 2, we have 50% complete response rate, 6 out of 12 patients, 7 out of 12 patients had and what we're calling an objective response, which is the addition of the 1 partial responder and 10 out of 12 patients had fewer interventions in the year after compared to the year before. Another way of measuring in a semi-objective fashion. The response is to try to quantify the disease based on endoscopic exam, and this is done with the Derkay score. To make this explanation very short, a Derkay score is calculated by the surgeon or the clinician examining the patient, and it's based off visual quantification of the disease. So we scope the patient in clinic, we'll show you some of these scope exams, and we use a standardized scale developed by Craig Derkay, many decades ago, which objectively quantifies the amount of papilloma. Next slide. What we see here is for 11 of the 12 patients treated at dose level 2, the pre- and post-treatment Derkay score, again, objective quantification of disease burden. This would almost be the equivalent of your RECIST criteria, if this was a cancer. The post here is 24 weeks or 6 months after completion of the clinical trial. Of course, there's data points in between the pre and the post, but I think this highlights the dramatic reduction not only in the need for clinically indicated interventions, which is the most important outcome measure for a clinical trial like this, but also quantifies the reduction in disease burden seen with this clinical trial. Next slide. The Voice Handicap Index score is a subjective scoring method basically, patients come in, you hand them a validated 10-questionaire that gives the patient the opportunity to express how much voice handicapped they feel like they have. If they have significant voice handicap because they had heavy papilloma disease burden, their voice is going to be really dysfunctional and they're going to score high on the VHI 10. And as their voice gets better with papilloma disease improvement, their VHI 10 score will decrease or improve and again, what we see here at a very similar pattern to what we observed with the objective Derkay papilloma scoring is the patient's VHI 10 scores, which again is their assessment of their voice quality significantly improves. As Dr. Sabzevari had described before, if a patient has preexisting immunity in the form of antibodies that will bind and neutralize adenovirus that can neutralize the vaccine before it has a chance to exert its positive benefit. What we've measured here are neutralizing antibodies against this vaccine specifically over time, measured after repeat administration of the vaccine. And what we observe is overall very low antibody titer development against the vaccine that does not increase over time with repeat administration. This is profoundly important and we would expect neutralizing antibody tighter levels that would actually neutralize a therapeutic vaccine like this to be in the 6,000 to 8,000 or even greater range. So what we're observing here is very, very low neutralizing titer response with repeat administration which is great news because it basically expands the window of possible therapeutic activity for the vaccine. All right. We're spending a lot of time and effort in trying to understand, why did we seem to have, I'll say, cure, why did we seem to have complete responses in about half the patients and not have complete responses than the others? This is a great question. What I can tell you objectively is there are no obvious differences clinically between these patients. No difference between whether a patient has HPV 6 or 11 disease, no difference in gender or age or disease severity. But we do observe very clear differences in our scientific correlative analyses. And what I can tell you in a nutshell is it seems like the HPV virus is behaving very differently within the papilloma cells between the responders and the nonresponders and one way that, that manifests is that T cells that are activated by the vaccine seem to have a hard time getting into the papilloma in patients that are nonresponders but they do a very good job at getting in the papilloma and the responders. And what you're looking at here on the screen are photomicrographs of multispectral immunofluorescence were we can actually measure the density or the infiltration of T cells coming into these papillomas. And then one of our responder patients, on the left-hand side, you can see very little yellow or green T cells. What you see on the right, after treatment is significantly enhanced the filtration of yellow green T cells. These are the types of coil of analyses that we're doing moving forward, and we expect this data to be very soon both in presentation and publication format. Let's do a few case studies of some of our really nice responders. So this first patient, we're going to go over subject 5. This is a 40-year-old male. He [ tries ] to work. He has a family. He lives far from his otolaryngologist who takes care of him in the Northern Midwest, and he was driving multiple hours very frequently to get clinically indicated procedures because this papilloma was wrecking his voice. In the pretreatment endoscopy image in the upper right-hand corner, you can see those bulky papillomas growth really covering both of its vocal cords as well as different parts of the voice box above the vocal cords. In the right-hand side, that his is 6 months after completing the clinical trial endoscopy image. That is a completely normal looking voice box. You could show that to any otolaryngologist in the United States, and they would tell you that's a completely normal voice box. He went from requiring 8 clinically indicated procedures in the year before the clinical trial to requiring none since, and he is now over 1.5 years out. The plot you see with the blue and red lines on the left-hand side is basically his Derkay and VHI scores, indicating they're very high pretreatment and essentially went to normal post treatment. In the lower right-hand corner of this slide is our scientific measurement, specifically of HPV-specific T cells in the blood and that left-hand blue plot is showing the very high response to HPV gene products in the T cells in the blood. The way that we test these T cells is we have the ability to test them specifically against the parts of HPV that are encoded in the vaccine. These are not random HPV-specific T cell responses. These are vaccine-induced T cell responses. And this patient, we also had the ability of looking at HPV specific T cell responses in the papilloma tissue itself and those blue dots in the right-hand plot on the right side of the slide there, show the basically increase or change in HPV-specific T cells that occurred after treatment compared to before. Next slide. Here, we're going to show two videos of this patient. The first video is his pretreatment endoscopy. I think this is only going to play for a few seconds. You won't hear me while the video is playing but as the video gets played, the scope is going to go down the back of the nose, and you'll have an opportunity to look around the bottom of the throat and the voice box and you'll see his voice box covered with bulky papillomas, pretreatment video. [Presentation]

On the right-hand side of the slide, this is his 6-month post-treatment video, again, 6 months after completing PRGN-2012, let's look at that video and contrast the appearance of his voice box and vocal cords now with no papilloma. [Presentation]

Because we've taken their life from someone who is having surgery every 6 to 8 weeks. Spending all their free money on cost for surgery that insurance didn't cover, not being able to work, not being able to communicate with friends and family, we've turned their life around. A few things are more satisfying than that as a clinician. Next slide. So case study number 2, that's actually a 73-year-old female. You can see the appearance of her voice box in the pretreatment endoscopy video. She has less bulky papillomas, but more carpeted covering of almost her entire inside of our voice box, both vocal cords. She essentially could not speak, when you have papillomas covering your vocal cords, it's difficult to close your vocal cords, what you need to do for coughing. So this patient was actually having a lot of respiratory issues related to anybody that clear secretions from her wind pipe. The post-treatment endoscopy video on the right-hand side, again, is 6 months after completing the clinical trial. This patient required 10 interventions in the year prior to the clinical trial. She is 73 years old. 10 anesthetics for a 73-year-old. That could kill you, just the surgery itself. She went to having no intervention since then. We've changed their life, she actually lived 10-hour drive away from her home laryngologist. That's a big deal for her to have no interventions in the year after. Again, there, we see her baseline Derkay and VHI scores. Pretreatment now significantly reduced after treatment. And again, in her induction -- actual measurement of induction of HPV-specific immune responses in her peripheral blood in that lower end hand plot. Next slide. Last case study we'll go after that we'll talk about today subject number 11. This is a 48-year-old young woman from the south who has a young family at home. She's actually a speech language pathologist which is a little bit ironic because those are people that deal with voice. You can see in the pretreatment endoscopy video, she had this monstrous papilloma originating from her right vocal cord. It completely inhibited the ability of her vocal cords to close. She could not talk. She was having trouble breathing. The post treatment is again 6 months after completing the clinical trial she acquired 8 interventions in the 1 year prior to try to control the growth of that papilloma. She's had no intervention in the clinical trial since and she's now over 15 months out. Again, on the left-hand side, we see the plot of her baseline VHI voice score and Derkay score quantifying our disease papilloma that was very high pretreatment and is basically normalized to baseline levels post treatment. And again, in the lower-hand corner, induction of peripheral blood HPV-specific T cell responses. Next slide. All right. I went through that really fast. I'm looking forward to a lot of good questions. But in summary, repeat administration of PRGN-2012 is very well tolerated. Grade 1, Grade 2 adverse events. We really tell people not much more than what you'd expect to experience with the flu shot, no dose-limited toxicities. Phase I efficacy data shows strong response in RRP patients. This is a very aggressive, heavily pretreated patient population, 50% complete response rate as defined by no interventions required since completing the clinical trial, 83% of patients treated at dose level 2 required fewer surgeries after compared to before. We see significant improvement in the Derkay score, the quantification of that disease burden and the VHI 10 score, which is the patient's subjective measurement of voice handicap. We are seeing robust induction of HPV-specific T cell responses, both in the peripheral blood and the papilloma really validating the mechanism of the vaccine. We do not see the development of high titers of neutralizing antibodies, which is great news, both for the repeat administration of the 4 doses on this clinical trial as well as opening up the idea of possible retreatment in the future. Phase II study is ongoing. We've treated a total of 32 patients and that 12-month post data is maturing now.

Thank you. Thank you so much, Dr. Allen. I'd now like to turn the call back to Dr. Sabzevari for some additional commentary on the trial in...

Thank you very much, Steve. Based on what you have heard, we have done some research, both with publicly available sources as well as internally commissioned third-party research. And as part of that research, there was an outreach to obviously, number of KOLs besides Dr. Allen and what we have heard from the KOLs really localizing is that they see the PRGN-2012 is considered as a paradigm shifting for the patients with RRP. What are the reasons for that? Number one was what Dr. Allen pointed out, the mechanism of action as it has been believed that really the only way to move toward the cure for this patient is to build a T cell response that is very specific to HPV 6 and 11 that can deal with this chronic infection continuously. The second reason for them was the reduced need for surgery. Again, as Dr. Allen mentioned, not only for patients that every reduction even by one surgery means a lot, but also the surgeons, they don't like this, and they don't appreciate and they think this is a game changer. It has a very reassuring safety profile, as Dr. Allen pointed out, it's similar to receiving a flu vaccine basically. And finally, it's the ease of administration because now you have a drug product just like a flu shot, you can give at offices actually, of the physicians and surgeons. So with that in mind, we also looked into the number of cases, both in United States as well as ex U.S. And it's estimated that there are 10,000 adult cases in U.S., 6,000 juveniles and ex U.S. it's up to 60,000 adult cases. However, there is not a good research being done on the juvenile and that's part of the ongoing future studies that we are doing. The projected market for the U.S. in excess of $1 billion. And the global market for this, it's projected to be around $2 billion. One of the things that it becomes very important, and Dr. Allen mentioned, it's the continuous requirement of these patients for surgeries over a period of time, which can be in hundreds of thousands of dollars, a lot of work, the income that has to go toward the medical cost that these patients have, this can be millions for patients. And in some of the actually publications, it has been reported per year upwards of $140 million for this patient population in U.S. alone. So with that, I would like to now invite our audience for their questions, and we would be happy to take your questions.

I'll be conducting your question-and-answer session. [Operator Instructions] Our first question today is coming from Jennifer Kim from Cantor Fitzgerald.

Congrats on some really impressive data today. I have two questions. The first one is to Dr. Allen if this type of systemic therapy were approved in RRP, in which patients would you consider using this? And specifically, is it patients who you're currently using off-label systemic therapies with or is this something that could expand which patients you consider for adjuvant therapy? And I'll save my second question for later.

Yes. I think if this gets an FDA registration, there's going to be a box indication and the clinical trial that we've done is patients that require three or more interventions in the year, which our best estimate is that probably captures about 1/3 of all the patients. Those are the patients that certainly could benefit, and those are the same patients that are the ones who are using these off-label potentially high toxicity drugs such as systemic bevacizumab because there's no other options available. So my hope would be that patients for example, receiving systemic bevacizumab could come off that and try a therapy like this, that would be the sincere hope.

Okay. Great. And my second question is to the company. How are you thinking about pricing given the impressive efficacy and safety profile? And then I was wondering the scientific correlative analysis that Dr. Allen talked about, is that something that could be used early on in treatment? To see who might be a potential nonresponder versus responder?

In regard to the pricing, I think this is -- we are not making a comment on that. Of course, one thing that I should say, this is a rare disease. And within the rare disease, as you can imagine, there is a range of prices that is associated with that. And that is something to come and we are looking at that in -- based on the modeling that has been done, you can go through the range, and you can see where it might be. But obviously, this is something for later on, for sure, as the we get, hopefully, approvals in the future and moving towards commercialization. In regard to the using the biomarker and I think this is very important, clearly, the correlatives that you see, first of all, is extremely important in showing the mechanism of action of this vaccine that exactly what we anticipated that this vaccine should do is actually doing in this patient. And especially creating enhanced and robust specific T cell responses to HPV 6 and 11, and that's very, very important. And by the way, a durable response, right? Because you have seen now that the patients that have a complete response -- they have a minimum follow-up of 12 months and actually up to date, they are ongoing the response. So that's -- I think that's important from that perspective. And to the point of biomarkers, you're absolutely correct. The biomarkers can be used early on in conjunction, of course, with what we see as an efficacy and establish not only the course of the treatment, but one of the things that I think Dr. Allen can speak to much better, for instance, in the patients that they have not fully -- they have a partial response or have not responded with the safety that we see here, it can also, as a future studies go to repeat dosing which currently, as you see, we have only one course of treatment, but that can be expanded for the future.

Next question is coming from RK from H.C. Wainwright.