Okay, we'll go ahead and get started. My name is Ben Burnett, biotech analyst here at Stifel. Pleased to have Helen Sabzevari, President and CEO of Precigen. Thank you for being here.
Thank you so much for having us, Ben.
Let's kick it off. Maybe just give a quick overview of Precigen and kind of some upcoming milestones that we should be looking at.
Absolutely. So one of the very important milestones for us is our program in RRP PRGN-2012, which, as you know, we received a breakthrough designation, first company that received a breakthrough designation, as well as the accelerated path the FDA recognized based on the data that we presented from our phase I with 50% complete responses in this rare disease. They have allowed us now, and given us the accelerated path without running any randomized trial and based on our phase I, phase II data, which is a superior data both on the safety and, 50% complete responses, which is very unique for a patient population, that they have had basically zero treatment for the past 70 years. It's not that of a lack of trying of investigators. They have tried many things, including all the checkpoint inhibitors, and unfortunately, it failed.
This is the first of its kind of a treatment that a vaccine that can address this with 4 vaccination. Now, we are getting to 50% complete responses. Patients do not require any surgery for 12 months, and the durability of response is quite high. So we are really excited about this and moving toward the BLA in the next year.
Okay, wonderful. It's a great place to start, and I want to get into this, but maybe just for the folks that are less familiar, what is RRP, recurrent respiratory papillomatosis? What is RRP, and how does... What's kind of the mechanism of action of PRGN-2012?
RRP, as you mentioned, these are really benign tumors that they keep reoccurring because of the infection of HPV 6 and 11 in the tissues of this patient. Where it occurs, it's really horrendous because it's either on the vocal cords or in the airways and trachea. These patients, for the past 60-70 years since the RRP was really diagnosed and realized what was the disease, they have had no option except repeated surgeries. These repeated surgeries, we have had patients that they have, per average, four-six weeks a surgery, and some of them since childhood, since they have been three years old. I think it's a horrendous disease, a rare disease.
However, the root cause of this is infection of HPV 6 and 11, and one of the reason that the treatments up to this point have not been really addressing the issue is because they have not been able to mount a really great immune response to clear the infection completely, and this is the first time that PRGN-2012, our vaccine, has been able to do this.
You know, so surgery is done at some time. So why isn't that curative? Why, why does it come back?
Because the underlying tissues, they are all infected.
Okay.
Surgeons can only basically take so much tissue out, and it's dangerous. The patients have to go under anesthesia.
Mm.
Imagine every four weeks, you take your child and has to go under anesthesia to clean up the airway or to clean the vocal cords, which is a very, very unique area. And as a result of that, even over the years of surgery, now you are building up these scar tissues that makes the situation even worse, whereas the infection is still in the body because this infection takes place in children when they pass through the birth canal, and in adults, obviously, through the interactions. If you don't basically address the root cause, then it keeps coming back, and surgery is like putting a Band-Aid continuously on that.
Mm-hmm. Okay. And then maybe just to kind of help us sort of frame the market opportunity for your asset, you know, I think some of the discussions we have with folks is, you know, should we look at patients with tracheal involvement or not? And does that distinction matter?
Yeah.
Maybe could you talk about that and just kind of talk about your overall thoughts and sort of the market opportunity?
Sure. Currently, our vaccine have been addressing the patient population, actually the most severe one, because we thought if we can make a difference in this patient population, obviously going to a lower and less severe disease, it will become much easier, right? So these are patients that they at least require three surgeries minimum per year, and majority of our patients actually in our trials have had far more than that, close to 10, actually. And, where the market opportunity, it... Our patients have had both tracheal, the airway obstruction, as well as the vocal cords. So currently, the patients that we have enrolled have enrolled on both sides, and our drug, drug has been working on both.
Okay.
We are looking forward, obviously, as we expand, and more patients come, but clearly, at this moment, we believe that it can be applied on both directions.
Okay, fantastic. I guess just kind of digging into a little bit on the efficacy, which you started out with, I think you talked about a 50%-
Yeah
... response. And I think that's it. Is it on an adjudicated on the number of surgeries or the frequency of surgeries that are done. Kind of walk us through that endpoint, and I think there's a couple other endpoints too that are using this.
Yeah.
How does your data look there?
I think, originally, when you speak to KOLs, or surgeons, that they treat these patients and all the patients, they consider if you improve by one surgery, you have done tremendously because they have no other option. However, what we wanted to do to make sure that the patients, they really benefit from this, and we address scientifically the root cause. And we have the platform, the gorilla adenovirus, which is unique to Precigen, and no one else has, which allows you to repeat it, given the, in a repeated fashion, and also is quite a large capacity for presenting various epitopes, especially on HPV 6 and 11, and even the new epitopes that we have found and included in that. So this was the opportunity to address, really, this disease at its best.
And then we decided, why don't we look at a complete response? Meaning that this patient don't require any surgery for at least 12 months, instead of just reduction in the number of surgery. So if you look at our response rate, if you take reduction in the number of surgery, we are standing close to 84% response rate, which is huge. If you are looking at the complete responses, we are looking at 50% of these patients. They have responded, they have not required any surgery. And one more sort of really, differentiation that we have. We are now well, some of our patients are past two years post-vaccination, and they have not required any surgery to this one. So we have a very durable responses.
Mm.
Is this a cure? Obviously, we are following these patients, and we will see that, but it's quite exciting to have a drug that you vaccinate in the arm, like when you give a flu vaccine, with the excellent safety profile. The safety profile, some of our investigators say it's better than a flu vaccine profile. Then having this kind of response, and that was one of the reason that the FDA, based on the data and the immunological data, granted us very rapidly the Breakthrough and accelerated approval.
Okay, that's great. You know, I think a lot of us are also trying to understand kind of the competitive landscape in RRP, and there's another asset in development. Maybe could you just talk about that landscape and sort of how do you see this positioned?
Absolutely. I want to be very clear. We are very differentiated on many levels from the competitor. First, number one, we were the first company that received this designation from the FDA in the July, August of this year-
Breakthrough.
Based on a breakthrough, as well as accelerated-
Okay
... approval. First, we received in July the breakthrough, and in the beginning of August, we received the accelerated approval. Second part of this is our drug from the safety and efficacy, according to what has been reported by competitors, it's far superior.
Mm.
We are standing at 50% response rate, complete responses, whereas the competitors not showing all of the data, but they are looking at 28%, and their durability of response is not, has been not established. We have very clearly said all of our complete responders have are staying in response and have durable responses, and now some of them have passed 24 months. Some of them are getting closer to that. So that's very another distinction in data and efficacy and safety. More importantly, also, our drug is given like a flu vaccine. It's a shot in the arm. It can given in any office, does not require any kind of a device, and it doesn't require a device approval path.
As you know, when you have a device and you have a drug, you have to go through the both approval path for that. And we are basically, it's very simple, and this is one of the... Actually, I think you were one of the pioneers when you had the chat with the KOLs in this field, when they were mentioning how excited they were about the drug. And I think in the past discussions that you have on RRP, one of the first analysts that spoke about this, and really pointing out or the KOLs, that this is paradigm shifting for them, the efficacy and the fact that you don't have to electroporate something into a patient, which also it's quite painful.
One other aspect of our differentiation clearly is we have been in a much more severe patient population. We started with the patients that they had three or more surgery requirement, and clearly, it's a very robust data set. We feel very excited about this.
Excellent. Okay, and you kind of touched on the regulatory path here. What is the regulatory path for 2012, your asset? And can you talk about some of the recent feedback you had from the FDA?
Absolutely. So as we mentioned, we received a breakthrough in July, which allows us a very close interaction with the FDA to have to make sure that we have full alignment. Based on the BLA accelerated path, obviously, we get the accelerated review, the rolling BLA submissions.
Mm.
We have been having very, very good interactions with the FDA. Originally, on the side of the clinical, and that's why, based on the data, they granted us the accelerated path based on our phase I, phase II. I should mention, we have finished our phase II enrollment. We are in the follow-up, and we will be reporting on that end of the first quarter, so or beginning of second quarter of 2024. One aspect that is important, that's a single arm, which means that we are seeing the clinical data as we are moving forward. We are very excited about reporting the data in early 2024, and that will allow us. Meanwhile, FDA has also agreed with our confirmatory trial, which is exactly what we have done in a phase II.
One other aspect, which is such exciting, and it really speaks to the alignment with the FDA. The FDA, based on the data, asked us: "Would you also consider repeat dosing for the 50% of the patients that they haven't had a complete response, and expand your label?" So that's a great, I think, position to be in and discussions with the FDA. So I think, and on a CMC level, our CMC manufacturing, as you know, is done on the site, so we are not dependent on other manufacturing for our commercial manufacturing, and we have been in discussions with the FDA, and we are well aligned on moving with our CMC manufacturing. So it's gonna be an exciting year for Precigen-
That's great.
and our investors.
Okay. So I guess if all these kinda go as planned, with the phase II already enrolled, so that'll finish next year. So it's like CMC is on track. Like, when could this be on the market?
We are obviously pushing forward very fast, and we are hoping that we are on the market in 2025.
Okay, excellent. And I guess one more question on this program, and if there's any questions from the audience, feel free to jump in. What did the KOLs say on kind of what durability they would like to see from a single course?
Yeah. The this has been something that our KOLs are really so excited about because there is very few drugs that you can give it with the safety profile that PRGN-2012 has, and with the efficacy of 50% complete responses. And two years in a patient population that perhaps every four to six weeks, they required a surgery, this is something that they say they have never seen before, and they are very excited about it.
Because unlike what people feel, surgeons, especially with this disease, they don't like to do the surgeries because these are difficult surgeries, and they are taxing on the patients, it's taxing on the surgeons, and they know that they have to come back every few weeks or few months to repeat this, and this is also very difficult on them, and they are really excited about the possibility of a cure. Because we don't know. We are, of course, following. As I mentioned, some of our patients in two years, some of them are getting close to two years, but none of the complete responders have fall out. They are all in response.
Awesome. Okay, and maybe just one more. I know this is probably, probably too early for this question, but, is there any, any line of sight on what, like, kind of pricing levels could be for something like this, with this sort of-
Yeah
durable and kind of high-efficacy profile?
Absolutely. So, our new head of a commercial has joined us, Jim Shaffer, and he's obviously digging very much into all of these aspects. But in the preliminary data that we presented for the modeling, the market in U.S. is around the adult patient and pediatric, we have 16,000 patients, perhaps with around 1,500 getting added on a monthly basis, and the market prediction for the preliminary was $1 billion. And then ex-U.S., you're looking at 60,000 patients on adult. We don't have a really a clear numbers on pediatric population, and this is one of the things that our groups are doing the research on. And if we add that, it's estimated will be close to $2 billion-
Okay
-market.
That's great. So maybe sticking with this platform, PRGN- 2009 recently had some data in HPV-positive cancers. I think it was just disclosed at ASCO.
Right.
Talk about that and kind of the path forward for that asset.
Yeah, absolutely. So if I just can add one thing before I-
Please
... go to PRGN-2009. On PRGN-2012, since it targets HPV 6 and 11, genital warts, which is another indication that is caused by HPV 6 and 11, it's also... You can imagine that this drug can very well move into that direction, and we are planning to do that. The associated market or number of patients in U.S., that it's—this is conservatively, it's 20 million. It's an upside of $3 billion market in U.S. And of course, you can imagine—ex-U.S., what would that be? So based on that, we—that's another plan and expansion on, for PRGN-2012. 2009, it addresses the HPV 16 and 18, which causes the HPV-related cancers such as cervical cancer, head and neck, and anal cancer.
This year, we received, again, approval for IND on an adaptive, phase II, phase III type of a trial design for cervical cancer, which we will be starting any day now, and we will, announce that. As you can imagine, the HPV-related cancers are somewhere between 5% of all cancers. The market for cervical cancer alone is $6 billion. For head and neck, you're looking at $9 billion, and if you look at what is, available, the Keytruda, at this point, it, it stands at 50-15, 15% response rate in cervical and 18% in, head and neck.
At ASCO this year, we reported on the same platform that we have used with PRGN-2012, the result that we had in HPV cancers in combination with the checkpoint inhibitors, and we reported 30% objective responses in stage four cancers, which is well above anything that's available currently. And, we are very excited about this program and moving forward and hoping to give the first set of data on that end of next year.
That's excellent. And will that, will that new data include the sort of newly diagnosed oropharyngeal squamous cell carcinoma?
That we will be reporting on that one as well. That is a separate trial.
Okay
... that is ongoing, and as you can see, we are moving these drugs, and not only... Obviously, we start at the later stages, but we are moving them much to earlier stages. And, for instance, the combination with the checkpoint inhibitors on a cervical cancer, the reason that we are using a checkpoint inhibitor and Keytruda, as I mentioned, it stands at the second line with 15%. Now, imagine the number of patients that obviously fail the first line, and then second line, 15% is really so low, and, currently, what we responded in our phase 1 and expansion phase was 30%. So we are really excited about that opportunity.
Okay. Is that why you switched from bintrafusp alfa? Okay.
Exactly, because bintrafusp alfa was not approved for basically in the second line, and anti-PD-1, the Keytruda and likes of it, is approved. So I think that was a decision. The mechanisms of actions are similar. However, we wanted to make sure that we get into a standard of care on a second line.
Okay, that's great. I do want to touch on some of your other programs in CAR-T, but since you did mention for 2012, this kind of expansion opportunity beyond RRP, I would love to ask. I mean, I have to assume that the company is very focused on the RRP-
Right
... and prosecuting that, but do you have any sort of sense as to when a study in these other indications could get?
Yeah, we are working on this, and I would say because it's such a huge opportunity for the company, clearly we are putting the ducks in a row to move very rapidly as soon as we submit our BLAs and, making sure that, of course, we have met the requirements for our PRGN-2012 because we are really laser focused on that.
Mm.
Then we will go for the expansion of the labels to these-
Okay
... other indications.
Okay. Go ahead.
Oh, thank you. For RRP, at what age are you considering beginning administering the vaccine?
For RRP, what age do you expect to administer the vaccine?
Okay. Currently, we are in adult population, so anyone above 18, and we are preparing. As you know, usually with the FDA, especially in the rare diseases, you have to show the safety and the efficacy in the adult, and then you start the pediatric, and that's what we are preparing also, and that will expand the label to the pediatric, which can be, as I mentioned, some of the children, they start from age of two to three even.
Please.
So if you were looking to prioritize the various 2012 opportunities for label expansion, being redosing, pediatric, genital warts, what would be the prioritization?
Okay. So definitely repeat dosing, the way we and FDA has really recommended, which I'm grateful to them. It will be an arm, a separate arm of a part of our confirmatory. So the confirmatory trial and the data, it stands by itself. This would be an additional arm that we have to enroll some patient. The ones that actually don't have a complete response, they just go to this arm, and they receive a repeat dosing. That data will be the basis for the expansion of the label, so that's what, how we are doing that. On a pediatric, it's a requirement, as you know, especially for rare diseases, that you immediately have to...
It's you get your approval, and you basically move with your commercialization, but then you put in your design and the clinical design for the pediatrics, which we will start in upcoming years, a year or so. And for the genital wart is something that obviously is very important to us, and the way we are looking at is once we have submitted our BLA, and meanwhile, we are designing those trials and then move in that direction.
Given the prevalence of genital warts, would you perceive that the N required for the trial would be larger than what you're looking at for RRP?
It all depends. From the perspective, it depends on, first of all, safety, which we have a very good safety already data, both from our phase I and phase II, as we are moving. And secondly, it all depends on efficacy because if you have a great safety and then you have a good efficacy. All of the treatments currently for genital wart, again, there is no really, the patients, this reoccurs continuously. It's just some ointments or some other things, and $3 billion market for treatments that they are not addressing the underlying problem in this disease, which was very similar to RRP. And we think that our basically platform can do that. So from that perspective, it's a discussion that we will have with the FDA, and I'm sure we will talk about that as we move.
We have done very well with the alignment with the FDA as we have moved. As you can imagine, we started these trials in 2021 in the middle of COVID, and we stand with the BLA in the summer of 2023. Accelerated it.
That's great. That's great. So in the last couple minutes, talk about the UltraCAR-T platform, and I think we're expecting some data next year, and including, you know, we're also watching the PRGN-3007 program, which incorporates some new technologies.
Mm.
Maybe talk about that.
Oh, absolutely. That's another platform that I absolutely love. We have taken... Maybe I should say something of really how we are differentiated, Ben, from the rest of the platform. We took some years to really address all the shortcomings of all the CAR-Ts. We wanted to develop a CAR-T, an autologous CAR-T, with the benefits of off-the-shelf, and actually better. We have seen what has happened to classical CAR-Ts, even the ones that has been approved. The manufacturing has become the center, now everyone talks about it. We start addressing this 40 years ago, the manufacturing, and how to move away. When people were talking about off-the-shelf, which is still not addressing the manufacturing, because can you imagine you have 100,000 patients, and you're manufacturing, even with off-the-shelves, we're addressing 50 people, and you can store.
Can you imagine global storage of these things, and still the payments of manufacturing, which requires lentivirus? What we have done is take the non-viral platform and move it from what I would say, a twentieth century non-viral to the cutting edge twenty-first century. What does that mean? We address the viability of the cells above 70%, which FDA requires. Even lentivirus has a problem with that, right? That's why there are failures is involved in that. Then, we address the transfection efficiency, because anyone that you talk, and if you have ever used a Lonza, for instance, electroporator, you have a few percentage. It takes hours to transfect maybe 10 million cells. And what we did is developed a semi-closed device, which we refer to as UltraPorator. This machine is capable of transfecting the T cells, 4 billion T cells, under 12 minutes.
So you can imagine that you can do multiple patients under one hour, basically. And if you have number of UltraPorators, then you can go to hundreds of patients within the same day. And one other things we have done, we have designed our UltraVectors that are transfected in such a way that they put a mechanism of membrane-bound IL-15, and not only the CAR of your interest, but your cells expand and persist directly in a patient. So you don't need to activate these cells outside, you don't need to have high cost of manufacturing and long time to get back to the patient. And this happens 24 hours. And when I say 24 hours, we start, and we release the next day autologous T cells of the patient directly back to them.
When we went to the FDA, FDA said, "This is a first in mankind." When we started in 2020, the trials, nobody thought that we can actually manufacture this. I remember the first talks, and Ben has been an advocate of this, and I have to say, an excellent vision, because in the past three years, not only we showed that we can manufacture according to the FDA, what they had asked us, continuously across different sites, but also we have shown now in our AML patient population, which we have the UltraCAR of CD33, almost 30% objective response last year in ASH. These are in a patient population that they have two-three months to live, and we can give very small amount of cells because these cells are not tired and exhausted. The objective responses have been between...
in patients that they have received anywhere between 10 to maybe 50 million cells, one dose only. The safety is very good. We have shown efficacy, and we have shown what the manufacturing can do. And this happens at the site of a hospital, so you don't have the manufacturing cost that is related to centralized manufacturing. And one other thing, in the new generation that we have added, we have added a mechanism that also silences the PD-1. So whereas all the other companies have to go in and combine now with checkpoint inhibitors, we don't have to do that, and the UltraCAR-T by themselves, they reduce that.
So we have this technology both in hematological, as I mentioned, AML, as well as in solid tumors, which is rapidly becoming very, very obvious to all of the companies that this is the next front for the cancer fight with the CARs, and none of the CARs can do that right now. We can do this in 24 hours, return your own cells back to you. One last final thing that I like to say about this, we can repeat those at a significantly lower cost. So I think this platform, the value of Precigen, is really, right now, it has a tremendous potential for the investors in the upcoming year. Not only based on our PRGN-2012, but also our UltraCAR platform that would give us completely new sort of way for treatments.
That's excellent. Well, Helen, thank you so much.
Thank you.
I think we're out of time.