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

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Hello. My name is Nick Abbott, I'm one of the senior biotech analysts here at Wells. It's my pleasure to introduce Precigen and the company's CEO, Helen Sabzevari. I can say to Precigen, a platform company with a novel point of care, autologous CAR-T, a novel gorilla adenoviral vaccine platform and a novel engineered oral bacterial platform, and all of which are in the clinic. So with that, over to you, Helen, for a short introduction. Then we'll go to Q&A.

Thank you so much, Nick, for having us. And I'm really glad to be here today with you and investors. And I just have to say that we will be making some forward-looking statements, so please pay attention to our slide on that as well as our Ks. So with that, I return it back to you, and we can start.

Sure. Okay. So this is sort of the adeno platform and HPV. You have 2 separate programs in HPV. How do you think about targeting HPV? I mean it's a relatively simple organism, 8 genes, but complex of 5 phylogenetic genera, alpha, beta, gamma. And as we've just heard, for COVID, new and new. So how do you think about targeting HPV?

So what we have done is a really advanced or AdenoVerse platform, which is a very different and differentiated platform than other Ad viruses, or in general, other viral. What is specific about this platform is that it's a library of various gorilla vectors that basically humans have not seen them before or have very little seropositivity. Why is that important? The importance is it allows you to do a repeat dosing, which, for instance, you are not able to do with the Ad5 and many other viruses. And that is important. Usually, the other viruses are given once. And that's all they can do because you raise this neutralizing antibodies or already existing ones, and they go up very fast, very high. And then basically is like you're shooting basically empty bullets. In this case, that will not be. And we have done tests on thousands of donors, healthy donors, looked at their seropositivity. And it is a nonexistent or very, very low levels. We did use these studies even in Africa, and we have the data. So that's one aspect. The other aspects about the AdenoVerse platform is the payload capacity that it has. You can express multiple genes, targeting different epitopes, many of them directly, and we can go up to 12 kb, for instance, and have a number of genes with the control switches, various cytokines be incorporated into this virus. Obviously, it's non-replicating, so it's safe. And it -- the studies that we have shown both preclinically and now clinically, it shows that by giving this, basically, the virus containing the genes of interest, you can increase your T cell responses. And this slide actually, it's a good comparison with other vaccines and the advantages that the AdenoVerse has, but also even with the TCRs. In a way, you are generating a specific T cell receptors to these epitopes directly without the TCR technology, which only targets one epitope at a time. It's a high cost of manufacturing. It has to be HLA restricted. This is off-the-shelf therapy. So we are really excited about this. And one other thing that we have done which is different than others and differentiate us, because of the payload capacity that we have as well as the bioinformatics databases that we have basically inside the organization, not only we are targeting the HPV-16 and 18, for instance, for HPV-related cancers, but also, we have identified other epitopes. So we have broadened now the target and increased the number of T cells, not only just through HPV-16 and 18 epitopes, but also others that previously have not known. And we have filed IPs on this, and we have this a vector that is very, very unique. So that's one of the advantages or many advantages that, I should say, this platform has. And as you know, we entered this PRGN-2009, which targets the HPV cancers. In August of 2020, we dosed the first patient in the midst of COVID. And we finished the Phase I dose escalation and reported preliminary and a safety dose escalation data in January of 2021. And we also show preliminary data that upon redosing and keep giving the virus, exactly as we had predicted, you keep increasing the number of specific T cell, unlike any other platforms like Ad5 that you cannot do that for instance. So those are some of the highlights of this platform and how we are using it to address the HPV cancers.

Okay. Terrific. You mentioned 2009. There's also PRGN-2012 for recurrent respiratory papillomatosis. I mean what are the differences? Perhaps -- I mean, the similarity is obviously they're both integral adenovirus. But what are the similarities and differences between those 2 products in terms of maybe the types of epitopes you're going after or the number of epitopes?

Absolutely. So great question, Nick. Obviously, the base platform now is being used in papillomas. These are sort of benign tumors that occur in trachea, larynx basically. And sometimes, in a respiratory in the lung, you see them. What is very devastating about this, basically, disease, as you well are aware, that this patient population, they concurrently, these benign tumors, they come up, these papillomas. And they require hundreds of surgeries in their lifetime. Some of the patients that actually we currently even have in our trial ongoing, every 6 weeks, they have to go into the clinic to be de-bulked and do the basically cleaning up and the surgery to be able to speak because it occurs over larynx and vocal chords. And it's devastating. And it happens both in children and adults. And what we have done is using the same platform, maximizing our portfolio and moving to 2012. In this setting, we are targeting the HPV-6 and 11, which is very specific. Basically, this is what is shared throughout the -- all of these patients with papilloma. Basically, you see an expression of that the cells are infected with either HPV-6, 11 or both. And this is very prominent. At the same token, what we have done very similarly, not only we targeted the HPV-6 and 11, again, we have broadened the epitopes. And we are targeting some novel other epitopes in our PRGN 2012. So we are maximizing the, basically, T cell -- generation of various T cells not only to the dominant epitopes of HPV-6 and 11, but others that currently exist. So it's very unique. And we are really excited about this program because the opinion is, the only way really is to reduce this number of surgeries or completion, hopefully, and one day stop them is by activating the immune system. And one aspects that, I should say, up to date, for instance, there has been a number of reports that even the checkpoint inhibitors were used in these studies, and they were not sufficient at all to change the course. And I think we are very excited, especially in November 14, our R&D, that we would be reporting on an interim data from this trial. And one aspects that I am really thrilled about is, again, we dosed our first patient this April. And we have been able to finish the dose escalation and enter to our expansion phase, which is really exceeding the goals that we had for this year for this program.

Yes. It probably highlights the level of unmet medical need that patients are queuing up for this.

Absolutely.

That's terrific. Let's maybe just go back to the oncology program. So you've got trials of monotherapy with bintrafusp combination. There's dose escalation in treatment both in the neoadjuvant and advanced setting. So maybe just summarize for us the cancer program in what we should be expecting in terms of their data and milestones.

Right. So as you mentioned, for PRGN-2009, we have finished the Phase I dose escalation and safety as well as the reports on dose levels and some of the efficacy, which will be -- the interim data will be presented again at our R&D Day. And we are very happy with one of the prominent investigators that will be presenting this in November. And at the same token, now we have entered to the dose, basically combination with bintra, we have dosed 6 patients with this. And we are hoping to present the interim data on that during November. We also concurrently have started our Phase II, which is in a neoadjuvant setting and for those individuals that have followed immunotherapy, I think one of the things that we continuously have to do is move our therapies to an earlier points in the patient's treatment and in front line. And this is a very good example of the kind of a trial that we basically are combining our PRGN-2009 and the standard of the care upfront and then following these patients. And I think this is going to be very unique. One other aspect about our PRGN-2009, now that we have the dose escalation and the safety from this, obviously, this allows us to open up to a number of indication and combinations. Bintra is one that currently we are looking at. But the reality is we would be able now from -- with this off-the-shelf basically HPV vaccine that we have, which is very unique, to enter to a number of indication, including especially the cervical cancers, as you know. Again, really these patients have nothing in front of them. Anti-PD-1 has been approved by only 15% response rate. So you can imagine, 85% of the patients basically have nothing to be used. And so we are in discussions with the FDA and how we can position our PRGN-2009 for a rapid move in the clinic and in combination, as well as not only in cervical, but also other indications such as head and neck and the anal cancer. So this is going to be applicable across various indications and -- both as monotherapy and as well as in combinations with other therapies.

Terrific. Earlier, you've mentioned the TCR therapeutics. And obviously, they've been tested in the HPV cancers and have largely failed. Is this because it's a single epitope, and here, you're targeting multiple epitopes, do you think?

Absolutely. I think you are absolutely on target on this. The TCRs, there are single epitopes, tremendous manufacturing for every one of them and then putting in one epitope or a few epitopes that they can cover, and it's HLA restricted, has to do with -- sometimes, it's not really applicable with the polymorphisms of HLA. And it creates a lot of the issues. And whereas with this system, now you have the ability directly to guide the immune system of the patient. And very specifically, because we have broad epitopes that we can put in the payload of this gorilla adeno virus, then it can really educate the patient immune systems directly within their own context of HLA to manufacture in a way internally their own TCRs and as many of them as they need. And I think that's what is very unique about it.

Terrific. Let's move to RRP. Both HPV -- why does one cause cancer and one not?

Lot of good questions. I think, obviously, in a benign settings, there is -- the concept of metastases, which is the really difference between when you consider a cancerous tumor versus a benign tumor, is that ability to move from one side to the other side. And so in these settings, you have these benign tumors that are reoccurring in the trachea, in the larynx especially and eventually some patients in the lung that they can have it. And it's the lack of metastatic ability of these that really focuses on it being benign. But they are just as problematic because if -- and we are showing a picture of this. For a patient that has the papilloma, imagine this is the trachea larynx of these patients. They can't talk. Breathing becomes difficult, and there is a lot of complication. So -- and if you can imagine that this patient has to go in every 4 to 6 weeks, for instance, for cleaning up, it's just unbelievable. This is -- it's just as bad as any metastatic disease in a sense of what the patients go throughout their life. And I think the difference here are also some of the pathways that are obviously activated during the cancerous tumors and metastatic pathways where here, those pathways are not specifically activated. But the immune component of the patients, for instance, the T cells, they are not being able to recognize and keep these benign tumors at bay, which is a similar situation that we have with the metastatic tumors as well. And I think that was very important. Currently, the KOLs, they really believe that the only way to overcome this is by activating the immune system and overcoming the suppression of the immune system against this HPV basically line papillomas. And what we are doing is exactly that, retraining the immune system of these patients directly with the PRGN-2012 to be able to basically recognize as these cells reoccurring and growing in the same side and basically keep the growth at bay so they don't need to go through this extensive surgeries.

Great. Now a hallmark of cancer, obviously, are mutations that drive resistance. Do we see mutations within these RRP lesions that might lead to resistance?

So I don't -- I cannot say that there are that many studies out there about mutation. There are few studies that have been done in regard to various HPV alphas and betas and gammas that has been seen. But it's not really pointing out that those other viruses are the cause. One thing I have to say, for papillomas, there is a very clear distinction that HPV-6 and 11, they are the baseline of the reason for this, basically, disease. As far as turning these benign, basically, tumors to a metastatic one to a cancerous one, I think there has been few studies that they have looked at it. Somewhere between 1% to 4% of the patients, especially the ones that have respiratory lesions, they have been reported that these lesions become metastatic or cancerous. And that has to do with some of the loss of the P53, for instance, pathway, so on and so forth. But in general, majority of the patients, they stay benign. And it's -- the treatments, it's just surgery for them continuously.

One last question on this, and we'll move to UltraCAR. So I think in the past, you've noted there are 20,000 individuals receiving treatment. Can you split that between children and how ever you define that, say, less than 12 adults? What treatment are they getting? And how many, I think, getting ongoing treatment as opposed to the 20,000? It's actually in a year, 40,000 get treatment, for example.

Yes. So I think currently, the treatment for all children and adults is exactly the same thing. And you can see how devastating it is because they all received basically the bulk surgeries. So that's the only treatment that currently exists. There's really nothing else. As I mentioned, they tried checkpoint inhibitors. They have tried others. All of them have failed, unfortunately. And so the way that we look at the patient population, and currently, we are moving this program, is very rapidly expanding. And as I mentioned, we are in a Phase Ib right now to get the data the way we are looking at and the trial. Originally, the expansion phase has been designed is, after the original debulking and this vaccination, we are looking at basically delay or even if we at all require surgery and how long that interval can be pushed basically. So if the patient requires surgery every 6 weeks, and now the patient keeps coming back after receiving these vaccines, and for instance, after 4 months still has not required any kind of a surgery, that is a huge win for this patient population. And so with that in mind, obviously, we want to fast -- move this very rapidly and discuss with the FDA from perspective of the design of the trial that basically allows us to go for a rapid approval eventually. And that's what we are doing. As you know, this patient population have no other alternatives. And so this would be at the center of our strategy to move this very, very rapidly with the right endpoints for the fast tracking it, and eventually, a BLA for the future.

So just clear on this. There's 20,000 individuals in the U.S. are receiving surgical treatment in -- during the year for their disease? Okay.

Yes, yes. All the individuals that have been basically diagnosed with this disease. Depending on the severity that they have, they might require various intervals of debulking. Some, it can be as bad as every month. Some can be having a surgery few times a year. But that's the only current treatment that exists.

Okay. Let's move to UltraPorator, which obviously is a very novel and potentially disruptive strategy for autologous CAR-T. And as you think about the UltraPorator sort of removes the rate limiting step of shipping cells to central manufacturing facility and waiting, whatever it is, 2, 3 weeks to get the product back. So what is the rate-limiting step when we consider use of UltraPorator?

I think at this point, our UltraPorator, I have to say, we are extremely happy about this the way it has been performing in the clinic. As you mentioned, this is really a disruptive technology for UltraPorator and the whole manufacturing. We really can electroporate and introduce billions and billions. So we don't have a rate limiting in a sense of, for instance, if you have 20 billion cells that -- which is incredible, and you want to transfect, this can be done in almost less than an hour. Every one of these cartridges takes, as you see it in the slide, we can do 3 billion to 4 billion cells under 12 minutes. And if you have 2 UltraPorator sitting, then you can do this simultaneously and cut the time to even much less than 48 minutes. So this is something that is extremely unique. And we have designed every aspects of this UltraPorator, including all the buffers and everything else that goes with this. And this is really -- we are very excited about the possibility of this in the field of the CAR-T as well as in other fields eventually to be used.

Great. One of the questions that I have as a microbiologist is always coming down to sterility. And so you've had discussions with regulators on QC testing. Is this considered a minimally manipulated product, like a lot of things in the blood lab? Or do you have to find a clever way to address sterility?

Yes. So excellent question. Clearly, by bringing in the UltraPorator, you have reduced the risks there. Because if you can imagine, any other electroporation device that is out there, if you want to do what we are doing, which is transfect billions and billion of cell, it takes -- just to give you a perspective, it takes anywhere between 4 to 6 hours. So you can imagine the risks of a sterility and mistakes and everything else, it just increases tremendously. Whereas with this machine, that's what it reduces. And actually, the reason that we start developing this was, in original discussions with the FDA which we had, that was the part that as we dose escalate, how do we make this platform commercially viable and scalable. And that's when we -- in discussions with the FDA, actually, we started this -- developing this platform and being able to get it to the clinic exactly as we were dose escalating. So definitely, that is part of it. But also in regard to the QC and the sterility tests, again, we have been engaging there at the very early on with the FDA to discuss that how can we rapidly do the testing of our manufactured product and infuse it directly to a patient. And obviously, the guidance that we and FDA have come down with, it has allowed us -- obviously, I cannot talk about the specific steps. But as you can imagine, within a few hours, the next morning after our electroporation, we are able to infuse the patients with this product and meet the FDA requirement.

So not to point you on the slide, Helen. And so just to be clear, then you're able to assess sterility from between electroporation to infusion the next day?

Yes.

Fantastic. Well, let's move to the first product then, the CD33 UltraCAR. I think you mentioned on the Q2 call that the November 4 presentation coincided with the release of the ASH abstracts. And since the CD33 is the target in AML, I don't think you have to be Sherlock Holmes to think one of those abstracts might be on PRGN-3006. So what do we -- what should investors expect as far as the abstract goes? And do you think there will be any significant changes between the abstract and the presentation?

So obviously, officially, I'm not going to make any kind of a comment on the abstract and where it will be presented. You mentioned and I -- but I will not comment on that. From the perspective, we definitely will present in this upcoming scientific meetings this year for PRGN-3006 as well as in our R&D. And we are going to be very actually happy to have our PI, Dr. Solomon, presenting at our R&D Day as well. And with that, I think it's going to be very exciting. Some of the dose escalations that we have done now, both in non-lymphodepletion as well as the lymphodepletion and -- will be discussed. And the -- not only the dose, the safety, the expansion persistence, but also looking at some of the efficacy data.

Perfect. And you mentioned efficacy. What do you see as the hurdle for Phase II, moving to Phase II here?

So again, I think we have to finish the dose escalation. And based on lymphodepletion and non-lymphodepletion arms, we are looking at what should be moved first or maybe both simultaneously, and then go to Phase Ib. Obviously, one of the reason that we had chosen the AML -- as this is extremely a difficult patient population compared to other hematological malignancies, these patients don't have really that much time and that they have -- especially the ones that are close to about 65 years, 3 to 4 months to live, which none of the other therapies really can manufacture and bring these things or cell therapies to that any kind of a treatment. So I think we will obviously move to Phase Ib. And based on the more data from the patients on a Phase Ib, we will be engaging with the FDA in regard to the path for the treatment of the patients for the future in this, basically, indication, very, very difficult indication.

Okay. Well, Helen, it's been fantastic. I think with such an interesting pipeline, we ran out of time before we run out of questions. But anyway, I want to thank you. I wish you and the team well and really look forward to the event in early November. Thanks.

Thank you. Thank you so much, Nick, for having us.