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Close to the Edge Episode 9:
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Close to the Edge Episode 9:
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ALEX PHILIPPIDIS: Howdy, and thanks for taking the time to watch Close to the Edge, the new video series from GEN Edge where we invite chief executives and outstanding scientists from groundbreaking biotech and pharma companies to sit down with us to discuss their science technology and their business strategy. I'm Alex Philippidis, senior business editor with GEN, Genetic Engineering and Biotechnology News, the publication covering the biotech industry for 40 years.
ALEX PHILIPPIDIS: Close to the Edge is an offshoot of GEN Edge, our new premium subscription channel from GEN providing in-depth exclusive news, interviews, and analysis of key trends in the biotech industry coupled with a range of multimedia offerings, such as this one. More details of our free trial offer are at www.genengnews.com/genedge. All one word, G-E-N-E-D-G-E. On today's episode, episode nine, we welcome Eric Ostertag, an MD PhD who is CEO of Poseida Therapeutics.
ALEX PHILIPPIDIS: Poseida is a developer of curative cell and gene therapies based on its own proprietary gene engineering platform technologies, which we'll learn more about during today's episode. Those platforms recently attracted the interest of Takeda Pharmaceutical, which has committed up to $3.6 billion toward a collaboration with Poseida that we'll discuss a little later in this episode. Eric, welcome to Close to the Edge.
ERIC OSTERTAG: Hi. Thanks, Alex. Good to be here. Thanks for the invite.
ALEX PHILIPPIDIS: Sure. It's been an exciting few years for gene therapy as a whole. How do you assess the fields of cell and gene therapy these days?
ERIC OSTERTAG: Well, I think the fields have come a long way. I was the first graduate from the, at the time, brand new gene therapy program at University of Pennsylvania. That was 25 years ago when I started. So at that point gene therapy was really more science fiction and it's, at this point, actually resulting in some functional cures for both cancer and genetic diseases. So it's certainly come a long way and I think the next steps would be to get those cures extended to more diseases and more people.
ALEX PHILIPPIDIS: Now, at U of Penn gene therapy program. I understand you studied under Jim Wilson, who has been involved with us at Liebert over the years, was an editor of Human Gene Therapy Journal at some point. A pioneer in the field, for sure. What was that like working in his lab?
ERIC OSTERTAG: Yeah, no doubt he is a pioneer. Some people might call him a godfather of gene therapy. And I did work in his lab very early on. I ultimately did my PhD in another genetics pioneer named Haig Kazazian, but Jim's lab was very early in gene therapy work. Funny story. One of the very first things Jim did when I started in his lab was he sat me down in his office and said, OK, when I was doing my MD PhD, I was worried I couldn't finish fast enough because every problem in gene therapy was going to be solved.
ERIC OSTERTAG: And the point of the story was to give me comfort that I should just take my time and do a very solid PhD. And of course, here we are 25 years later and finally, we're at the doorstep of very large successes in gene cell therapy.
ALEX PHILIPPIDIS: Yeah. So how did you get interested in molecular biology to begin with then, and pursuing a career in the field?
ERIC OSTERTAG: You know, I always knew I wanted to be a scientist even from a very young age, probably early grade school. I'm very fascinated with science and I guess it was probably high school I learned about genetics. That was from my friend's father who happened to be my biology teacher and genetics really just blew me away. I wanted to do it.
ERIC OSTERTAG: I knew I loved it and I asked the question, and I'm sure others were at that time, if cancers and many congenital diseases have an underlying genetic component, why not fix it? Why not fix the underlying problem rather than give somebody a drug every day or every week for their life? So that's the concept behind gene therapy. And I then went to University of Wisconsin where I'd already been accepted into medical school out of high school.
ERIC OSTERTAG: I still had to do college, but I was given conditional acceptance. So I didn't really plan on going anywhere else, but as I progressed through my classes I realized that the new idea of gene therapy was taking off and my advanced genetics teacher told me I really needed to look at University of Pennsylvania. Of course, that's where Jim Wilson was. And so I did apply late in the cycle.
ERIC OSTERTAG: I also wrote to Michael Blades, who has an MD PhD and was also a very early clinical pioneer in gene therapy. And he told me, look, if you want to do gene therapy you really need an MD and a PhD. So everything kind of converged on University of Pennsylvania and that's where I did my MD PhD and then ultimately residency and fellowship also.
ALEX PHILIPPIDIS: All right. You mentioned a lifelong interest in science. Was there either a teacher or an event that got you interested in the broader field of science?
ERIC OSTERTAG: Well, my father is a psychologist. My mother's a NICU nurse, my sister became a NICU nurse. So really the family's been pretty heavily involved in the medical side of things. And even my grandmother got her PhD, which at the time I think was a bit unusual, and so I think that's been a big part of my family and my life for as long as I can remember.
ALEX PHILIPPIDIS: And check me. From U of Penn you went to a few companies from PhenoTec to Vindico NanoBioTechnology, then Transposagen, which you founded. How did you get around in your early career into companies? Because these look like startups just hearing about them or at least early stage, for sure.
ERIC OSTERTAG: Yeah. It was sort of a path I didn't intend on going down. I thought I'd be a physician scientist like I trained to be in academia. And I had a great academic project lined up that was working really well during my fellowship and I was waiting for a position at Penn in my department, which would have been transfusion medicine. They have a leading department there. That's where you would take cells out of the body, but possibly engineer them and put them back in.
ERIC OSTERTAG: That's really where CAR T or chimeric antigen receptor T cell therapy came out of. And it was a series of events where while I was waiting for the-- getting a little bit of background there. While I was waiting for the opportunity, my mentor was starting a company called PhenoTec to use nanoparticles-- well, at the time it actually wasn't nanoparticles, it was a method to do blood typing.
ERIC OSTERTAG: And I started looking at nanoparticles coming out of University of Pennsylvania as a possible solution. So I became increasingly involved with sort of running that company both from the science and a bit from the business side. And I was also trying to move this technology I was working on, which is called a transposon technology, forward, but the tech transfer office there wasn't licensing it. And out of my frustration I said, look, let's just start a company.
ERIC OSTERTAG: I can run it, I'll write some grants, and eventually I'll hand it off to another CEO. But that eventually never happened, and here I am. So PhenoTec we actually kind of evolved into a company I co-founded called Vindico and Vindico was ultimately purchased by Poseida. So the company I founded, other company, was Transposagen. That grew very large and we spun out Poseida from Transposagen.
ERIC OSTERTAG: So they're really all related. They're all related entities.
ALEX PHILIPPIDIS: Hmm. So that spin out of Poseida from Transposagen took place in 2015. How and why did Transposagen and spin out Poseida?
ERIC OSTERTAG: Well, as I mentioned, Transposagen was very early. This was early 2000s where gene therapy was pretty early stages. The goal of that company was human gene therapy and we had full legal name was Transposagen Biopharmaceuticals. But I would say the technologies, ours and others, weren't ready for the clinic at that point. They were developing.
ERIC OSTERTAG: As you know, there were some setbacks early on in the gene therapy space. So while we were developing these really powerful genetic engineering technologies, we sold what we had and that was these same tools as reagents, and we would also make cell lines and animal models. Now that reagent business became quite lucrative. It was supporting the business. And so by the time we did a deal with Janssen J&J in 2014 in the early CAR T space, that's when I decided we should really split the companies because the parent company was working on a reagent business.
ERIC OSTERTAG: There were other applications like agriculture that we were working on and human therapeutics is, of course, just a little bit of a different beast. So I thought it would be better to split those companies by field of use, and that's exactly what we did, with Poseida having all of the human therapeutics.
ALEX PHILIPPIDIS: Mhm. How did that spin out company come to be called Poseida?
ERIC OSTERTAG: Yes. It's an interesting story. I mentioned there were a lot of different applications of these powerful platform technologies-- gene delivery, gene editing, eventually the nanoparticle technologies-- and so I didn't think one company could do all of it. And so by splitting the companies by field, one company that spun out was focused on the genetic testing aspects and CRO aspects. And that was named Hera after the Greek goddess of heritability.
ERIC OSTERTAG: So I thought it would be fun to name the agriculture applications Dimitra after Demeter which was her sister, goddess of agriculture. And there is only one sister left, Hestia. And Hestia is the goddess of home and hearth. I didn't really think that was a good description for where we were going with Poseida. So I look to the brothers. Zeus was kind of taken already, I think, in biotech.
ERIC OSTERTAG: Hades didn't have the right connotation. So I named it Poseida after Poseidon, the only other brother.
ALEX PHILIPPIDIS: Hmm. That's great. Now you mentioned in those early years of gene therapy, the field had been struggling to overcome, and Jim Wilson has talked about this publicly, the Jesse Gelsinger death in 1999. And for many years investors shied away from gene therapy and companies didn't get as far as they have in more recent years. How did that affect your own startups and even early Poseida?
ERIC OSTERTAG: Yeah, absolutely. So the work I did in Jim's lab was before Jesse Gelsinger died, and then I moved to a more basic science lab project on these retrotransposons called LINE1 because I knew that they could be used both they and DNA transposons as a nonviral DNA delivery technology. The other half of Haig Kazazian's lab was a very much pioneer in gene therapy.
ERIC OSTERTAG: It was working on hemophilia factor VIII, which is ironically today one of our therapeutics in our pipeline. Also irony, by the way, he discovered active LINE1 transposons because they caused a mutation in a child with hemophilia and here we are 30 years later possibly being able to cure the disease with a different type of transposon. Anyway, that, I think, was a good experience for me. I think it was the right choice.
ERIC OSTERTAG: But as you said, the early technologies were viral based and the problem with viruses, although they've evolved for millions of years to be good at delivering DNA into human genomes, the human has been very good at evolving ways to prevent this. And part of that is the immune system. Some of the immune reaction can sometimes be problematic if not fatal, right? So even then 25 years ago in Jim's lab, I was working on hybrid viruses to try to get the best of all worlds, to get something that would integrate stable into the genome, thereby allowing potentially single treatment cures for genetic diseases but to eliminate the immune reaction.
ERIC OSTERTAG: And at the time the idea was, well, you just need to keep stripping proteins and genes out of a virus until the immune system can't recognize it as virus. It was about that time I had the idea, well, why not just build something that functions very much like a virus but isn't a virus? And there are two halves to that. One is a gene integrating system, and that's your DNA transposon which I spent my PhD working on, and the other half is a nanoparticle.
ERIC OSTERTAG: That would be substitute for the capsid, which gets the technology into a cell, and there you have it. It's functionally similar to a virus, but it has many advantages over viral technologies. And that's precisely what Poseida is focused on, nonviral DNA delivery.
ALEX PHILIPPIDIS: Mhm. And you mentioned advantages of these. How would you sum up those advantages in Poseida's approach?
ERIC OSTERTAG: Well, in terms of piggyBac, for example, this is a DNA transposon that can deliver potentially large, cargo large therapeutic transients. So it's at least 20 times larger than even some of the biggest viruses that have large cargo like lentivirus or gamma retrovirus, AAV, of course, which is a classic virus used in gene therapy, is even smaller. It's only 4.5 Kb. And it's a safer integration profile.
ERIC OSTERTAG: It's about 40% less intragenic than lentivirus. So we say it's nonmutagenic, it's nononcogenic, like some of the early gamma retroviruses, and it is easy to make. It's just GMP DNA and RNA versus GMP virus, which is time consuming, costly. So it's faster to clinic, lower cost, and it works really in every single cell type tested. That includes dividing cells, nondividing cells, you don't need DNA replication.
ERIC OSTERTAG: That has some huge advantages in CAR T, for example, because we can get into a desirable cell type that you really can't achieve with the viral technologies. So that's the half of the equation I talked about, getting the DNA integrated into the genome in a way that is very safe and that the body doesn't recognize as a virus. So the second half then would be to encapsulate that in something if you're doing in vivo gene therapy.
ERIC OSTERTAG: If it's outside the body or ex vivo you can just use what's called electroporation, of course. Now for in vivo, you would package that. And if you put that in a biodegradable nanoparticle, the advantages of a virus are, one, you don't see pre-existing immunity so there's not a portion of the population you can't treat. Number two, you don't create immunity. So you, first of all, can redose if you need to.
ERIC OSTERTAG: You also don't get these whopping immune reactions, so it's a much better safety profile and it's easier to manufacture, lower cost to manufacture. And to top it all off you have this cargo capacity advantage then. So it's really got the ideal characteristics you would want to potentially treat just about any genetic disease or any oncologic indication.
ALEX PHILIPPIDIS: Mhm. So then what are Poseida's disease focuses and how and why did the company come to focus on cancer and genetic disease?
ERIC OSTERTAG: Well, again, I mean, it's just as simple as the original idea that if all cancers have some sort of genetic component and congenital diseases have some sort of genetic component, why not fix those? So we developed what I think are best in class gene addition technology. That's piggyBac. We have, I believe, best in class gene editing technology. We call that Cas-CLOVER.
ERIC OSTERTAG: And we have some best in class gene delivery technology. That's the biodegradable nanoparticles. And you can kind of mix and match those in any way to do just about anything in gene therapy, either ex vivo or outside the body-- CAR T would be an example of that-- or in vivo. So we try to pick indications that really highlighted the advantages of our technology. So for example, in the CAR T space we started with a hematologic malignancy which was multiple myeloma.
ERIC OSTERTAG: A little bit harder than what people were working on at the time, the B cell leukemia and lymphomas. We recently then move to solid tumor with some great success treating prostate cancer and then in the gene therapy side, the in vivo gene therapy, we started with OTC which actually was the indication that Jesse Gelsinger had. We think we can do that safely, effectively, and we can actually treat the pediatric patient population, which you can't do with the more classic AAV approaches.
ERIC OSTERTAG: And so that was a great proof of concept. And then the next indication, which we did partner with Takeda, was hemophilia A. The transgene there is factor VIII, which is really large. You can't fit that in a standard AAV capsid, so that was a great way to showcase some of the advantages we just talked about of going to fully nanoparticle technology.
ALEX PHILIPPIDIS: And we'll definitely talk about the Takeda collaboration a little later, but I wanted to learn more about the Poseida approaches to overcoming primary limitations of current cell and gene therapeutic. You mentioned a nonviral piggyBac DNA modification system and Cas-CLOVER and there also are nanoparticle and AAV based gene delivery technologies. What determines which approach you wind up using?
ALEX PHILIPPIDIS: Is it disease specific or what?
ERIC OSTERTAG: It is somewhat disease specific and it's also I would call it therapeutic modality specific. So for example in the CAR T space, this is an ex vivo form of gene therapy, meaning you take the cells out of the body, you modify them, and you put them back in. Now in this case, it's T cells. What we've learned is that not all T cells are equal. So maybe not surprisingly, not all CAR T products will be equal.
ERIC OSTERTAG: It really depends on the type of cells that you get in the final product. Now this is a somewhat new concept because the cell type that we use is called TSCM, for stem cell memory T cell. That was only really described in humans less than 10 years ago and here we are six years ago already making CAR T products out of it. It's a desirable cell type because it's the true T stem cell.
ERIC OSTERTAG: This is your self-renewing, long lived, multipotent cell that gives rise to all your other T cells in your body like your CD4 positive helper cells, CD8 positive killer cells, your T regs, they all come from this cell. Normally the nongenetically modified version of this cell would last a lifetime. So if you get infected with the virus these are your memory cells that years from now, if you get reinfected, they'll immediately start killing the infected cells.
ERIC OSTERTAG: So great cell type to have for a CAR T product. The problem is, the viral technologies really don't get into this cell type because you have to activate cells to even get the viral infection. PiggyBac doesn't have that problem. It goes actually preferentially into these TSCM cells. So what we've seen now in the clinic when you make a high TSCM product is it's associated directly with best responses, the percent of TSCM in your product.
ERIC OSTERTAG: It gives you some remarkably long duration of response. It can give you a better safety profile. And most importantly, I think, is that it works in solid tumors. And that's kind of a complicated explanation for why that is, but we recently showed, I think, the best results ever for CAR T against a solid tumor indication where we had complete tumor elimination in at least one patient out to six months.
ALEX PHILIPPIDIS: If you could talk about that, that's something that the company had discussed pretty recently. Some positive results.
ERIC OSTERTAG: Right. So the drug was called-- or product candidate, I should say, was called PPSMA101. And this is a autologous CAR T, meaning individualized therapy for metastatic castrate resistant prostate cancer. As I'm sure you know, prostate cancer is very common in men. It is somewhat slow growing when it starts usually and has some treatments. But once it progresses to what's called castrate resistant, meaning it's failed anti-androgen therapies, it's a very aggressive disease with unfortunately short five year survival rates of 30% or less.
ERIC OSTERTAG: So huge unmet medical need here, large number of men who have this indication. And so what we did is made a CAR T that targeted a molecule called PSMA that's very specific to prostate cells. These men no longer have a prostate because it's been removed, so there are really no other cells in the body that express this PSMA, or at least at levels that are recognized by the drug.
ERIC OSTERTAG: And what that means is you don't have to worry about on target off tumor toxicities. We've seen very nice safety profile so far with this product. And because it's expressed at high levels on the prostate cancer cells, you can get very good targeted killing of those cells. And again, I think it's mostly because of the stemness of our product compared to others.
ERIC OSTERTAG: You actually get a strong and durable response. These cells are thought of more like a prodrug. They can graft in the bone marrow and then they can make wave after wave of the drug, your effector cells. So they kind of chip away at these tumors and we've definitely seen that in a number of patients now. More than half of our patients have had PSA, which is a biomarker for this disease decline.
ERIC OSTERTAG: About a third of patients have seen substantial declines of more than 50%, and a couple patients, including the one I mentioned, have very drastic declines shown by imaging with one patient showing at least, by imaging and PSA levels and even a bone marrow biopsy, evidence of complete tumor elimination.
ALEX PHILIPPIDIS: Wow. So what happens or where is that prostate cancer candidate now in development?
ERIC OSTERTAG: We're going to continue with the clinical trial. Obviously that's very promising, and that would involve increasing the dose level, that would involve trying some other strategies like maybe dividing a dose into multiple smaller doses, and we've also then made or are working on in our pipeline a fully allogeneic version of this. This would be something instead of making it from a patient with prostate cancer, we make it from a healthy donor and it's an off the shelf product.
ERIC OSTERTAG: We can make, we think, hundreds of doses from a single donor. So you can imagine that drops the cost of manufacturing quite a bit. We actually increase the stemness in these fully allogeneic products and that, we think, will increase the desirable attributes I just talked about, this efficacy, safety, the duration of response. All of that would then be in a fully allogeneic CAR T and we've already launched a couple of these.
ERIC OSTERTAG: One is for multiple myeloma and just received safe to proceed from the FDA a few weeks back. We also have a second one for pan solid tumor, meaning we think this could treat many different types of cancers, including lung cancer, breast cancer, ovarian cancer. It's called MUC1C-ALLO1, and that has an IND later this year. And then the prostate cancer one I talked about will be following those sometime either next year or the year after.
ALEX PHILIPPIDIS: OK. So these still have a ways to go in the clinic then.
ERIC OSTERTAG: Well, yeah. Some of these indications are because of the unmet medical need such that you can do a phase I, phase II clinical trial with potential accelerated approval. So it is shorter than some types of drugs, but of course, the clinical trial process is regulated by the FDA and rightfully so you have to prove safety first. So they do take usually several years.
ALEX PHILIPPIDIS: And also interested in the Cas-CLOVER site specific gene editing system you mentioned. A little bit on how that works and what sort of challenges in gene editing, and I'm thinking of off target edits, that this would attempt to avoid.
ERIC OSTERTAG: Exactly. Great question. And likewise we were very early in the gene editing space, so the company, parent company, had talked about Transposagen had an early version of a TALEN, which we called XTN. We also had a one from a different genus called ralstonia called RTN. So we had a lot of early experience with TALEN creation, TALEN design.
ERIC OSTERTAG: And we had some notable people on our scientific advisory board that are leaders in the gene editing space like Keith Joung and George Church. So we were really following these advances right as they were occurring and we had the opportunity to license the zinc finger nucleases. Actually, one of my friends who unfortunately passed away, Carlos Barbas, had a big hand in creating the zinc finger binding modules for those.
ERIC OSTERTAG: So we were aware of them. They were very expensive at the time and they did have some downsides. And as you know, the field started evolving very rapidly. So first there were the TALEN technology which we were in. Then there was, in addition to the zinc finger nucleases, the ability to make these fully dimeric, and that's where Cas-CLOVER came from. That eliminates some of the off target problems with the TALEN so we call that TAL-CLOVER.
ERIC OSTERTAG: And then after that, of course, CRISPR. Huge leap forward. Easy to use, easy design, low cost, has multiplexing ability, but it's a very sloppy enzyme. It creates a lot of unwanted off target mutations. So we kind of combined a couple of those ideas. We took a completely catalytic inactivated Cas9 protein from the Cas9 CRISPR system. So it still can use RNA to get you to specific places in the genome, it's a ribonucleic nucleoprotein DNA binding protein, and we then fused that to this very clean nucleus, which the scientific name is CLOV051.
ERIC OSTERTAG: We call it CLOVER. So instead of TAL-CLOVER where we fuse that to a TAL array, we now had it fused to this Cas9 protein. And that's where you get Cas-CLOVER. Cas-CLOVER we found was really ideal. It had the best of all worlds. The low cost multiplexing ability of the CRISPR system, but with this exquisitely specific enzyme fused to it. It will only cut DNA if two half sites are present at the exact same place at the exact same time in the genome.
ERIC OSTERTAG: Now this is different than a CRISPR Nickase, which can still go to other places in the genome and create nicks and breaks. This does not. So it's very clean and it doesn't have the off target problems with some of the other systems. So that's what we've been using for our fully allogeneic CAR T programs. And of course, we could eventually use that directly as a therapeutic and that is part of the Takeda collaboration.
ALEX PHILIPPIDIS: Mhm. On the Takeda collaboration, it includes up to six liver and hematopoietic stem cell directed indications, an option to add two additional programs through Takeda, potentially up to $3.6 billion. How did Poseida and Takeda get together?
ERIC OSTERTAG: Well, we've been talking with Takeda for a while, so they've been aware of our technologies. We meet at conferences like JP Morgan Health Care. And the talks just started taking off more recently because I think they were, like us, interested in achieving what they call functional cures. We say single treatment cures. Single treatment really could mean a series of a few treatments, but the idea is you give one or a few treatments and you're done for life.
ERIC OSTERTAG: That's the goal. So philosophically we're aligned. We're also aligned, I believe, in the idea that nonviral gene therapy is the future. So they're dabbling in other areas for sure, but I think they view that nonviral is the future of gene therapy and there aren't that many nonviral gene therapy companies, especially those that have all of the components we do.
ERIC OSTERTAG: The gene delivery, the gene editing, as well as the biodegradable nanoparticles. So they were interested, I think, in all of those applications and I think they're a great partner. They, as you know, purchased Shire. They really cemented their position as a leader, if not the leader, in rare diseases. So they have certain expertise in rare diseases, certain reagents maybe we don't have access to.
ERIC OSTERTAG: We've got the gene therapy tools, genetic engineering technologies they were interested in, so it's really a great match.
ALEX PHILIPPIDIS: Well, what do the companies plan to do through the collaboration?
ERIC OSTERTAG: Well, a couple things. You mentioned the multiple targets, multiple indications for both in vivo-- so this is all in vivo. Hematopoietic Stem Cell, meaning HSC, your true blood stem cell, can be used to treat a lot of different indications. But you could do that ex vivo like I talked about with CAR T and T cells. This was actually in vivo. So if you take the reagents, injecting them, they go find those HSCs in the body and genetically modify them.
ERIC OSTERTAG: And the other is the liver directive, which we had already been working on. We have still pipeline programs like OTC101 that are not part of this collaboration, but then we have some new ones that they can choose. And it also is a research collaboration, so we're continuing to develop our programs. We talked about piggyBac, we talked about Cas-CLOVER, we talked about the biodegradable nanoparticles, but there are some really cool things we're working on like a site specific version of the transposes site specific piggyBac, and of course, they're very interested in that also.
ALEX PHILIPPIDIS: Sure. , Now does this collaboration signal a change in pesetas pipeline approach toward more partnered programs? I know up till now a lot of the programs have been developed wholly by Poseida.
ERIC OSTERTAG: Well, we were in what I'd call stealth mode right up until our IPO a little over a year ago now, and I think it was right after that that people became aware of how broad our technologies were and how many different things we could do. We had a 4 and 1/2 hour R&D day and that triggered a lot of incoming interest from pharma companies, including Takeda as one example. And yes, that was intentional on our part to realize that, hey, these technologies are so broad.
ERIC OSTERTAG: You could do just about anything you can think of with advantages in either ex vivo or in vivo gene therapy, but a single company can't do it all and can't do it for every indication. So this was intentional to start partnering. And another thing we like about the Takeda deal is that didn't give up a lot. We do have our hemophilia A program which was in our pipeline going into that, but most of this is for indications that were not in our pipeline.
ERIC OSTERTAG: And I think we can do a lot of additional collaborations both on the cell therapy side and the gene therapy side that are similar to that type of value creating deal.
ALEX PHILIPPIDIS: Among the programs still wholly owned-- and we talked about this earlier-- was the prostate cancer program. Now that program began a year ago with a bit of a hitch when the FDA imposed a clinical hold after a patient had died of liver failure after developing symptoms consistent with macrophage activation syndrome, which according to the company, was exacerbated by noncompliance by the patient. And that hold was lifted three months later.
ALEX PHILIPPIDIS: Poseida agreed to implement protocol amendments and what were some of those changes?
ERIC OSTERTAG: Yeah. So first of all, there was a patient, one of the earlier patients in the clinical trial, that unfortunately had SAE. They came in late with acute liver failure and we were not able to or the physicians were not able to save that patient. We do know there was a significant noncompliance, meaning they skipped several important follow up appointments because we were able to dose fully outpatient given the safety profile of our BCMA101 program.
ERIC OSTERTAG: We've just over 100 patients there with very low rates of CRS. We've never seen a grade 3 or higher CRS, never had a patient even need to go to the ICU. So uniquely in this space, we could do outpatient dosing. We started doing that with the prostate cancer trial. So what was unfortunate about that in a really tragic way was we now know the cells were actually expanding and when we look at the other patients in the trial, that patient not only could have been likely saved because of the easily treatable side effects that we now see rarely in other patients, but the cells were expanding and in all likelihood could have received a lot of benefit from that.
ERIC OSTERTAG: So we did make our own recommendations to the FDA and those included trying to solve this noncompliance issue by hospitalizing patients for the first 10 to 14 days after treatment so they could be more closely monitored. The same tests that we were doing would have picked this up and in fact, did. It just was unfortunate that the patient came in too late. So we increased the frequency of some of the testing. There was already a built in mechanism to de-escalate to a lower dose, which we did.
ERIC OSTERTAG: So we recommended all this to the FDA. They had not one single additional change that they asked us to do. It was one of the shortest clinical holds I think possible. It was actually just a tad over two months. And I haven't really seen any hiccups since then. So we did release some data as part of that was safety. We only saw three additional CRS, no grade 3 or higher, and easily treatable with standard therapies like tocilizumab.
ALEX PHILIPPIDIS: So some encouraging data reported in August. When's the next update expected in that study?
ERIC OSTERTAG: Next update we've said publicly will be in the first half of next year and we haven't said the exact meeting, but it would likely either be ASCO GU in February or ASCO the parent meeting a little bit later in the year.
ALEX PHILIPPIDIS: Mhm. And on CAR T, I know Poseida has likened its CAR T cell therapy to an ex vivo form of gene therapy. How so?
ERIC OSTERTAG: Well, it really is. Right? We talked about this, but ex vivo gene therapy is take a cell out of the body, in this case it's a T cell genetically, modify it-- I like to say educate it to kill the cancer cells-- and then you put it back in the body. So that's definition of classic ex vivo gene therapy. We talked about how ours is different. It's nonviral.
ERIC OSTERTAG: That allows us to get these high TSCM cells and nobody else can do that. And I think what it highlights though is that we can use these same technologies, the gene addition and the gene editing we talked about now, in other cell types. So we've shown that actually gene editing for hematopoietic stem cells, we've shown for iPSCs. Both of those were at our research day.
ERIC OSTERTAG: And another thing we have that I don't think a lot of people were aware of is we've made a lot of progress with the CAR NK program. So that's an example where we would probably partner that. It can be used in different ways as a sort of semi allogeneic cellular approach for cancers, and that's something that we will not likely pursue as a pipeline product but we could certainly partner it.
ALEX PHILIPPIDIS: For sure. And on the CAR T front, companies reported plans to file two INDs for the multiple myeloma and the solid tumor indication programs. How far down the road are those? Would those be next year or further down?
ERIC OSTERTAG: No, these are first of all fully allogeneic. We have very strong confidence in our fully allogeneic program now. And the fully allogeneic cells we've shown in very predictive animal models work even better than the auto version, which is not typically the case for our competitors but I think, again, the stemness is important to that. We can make hundreds of doses through something called the booster molecule.
ERIC OSTERTAG: So that gives us a huge advantage in manufacturing costs. So the first IND you referred to actually already was filed this year and already was given safe to proceed from the FDA, so in the very short near term we'll start dosing our first patients. And then the second fully allogeneic IND that you referred to is also this year and that is for a target called MUC1c.
ERIC OSTERTAG: I referred to this briefly previously, but it's a, we think, pan solid tumor target, meaning just about any epithelial derived cancer could potentially be treated with this CAR product. And when you say, well, what's an epithelial derived cancer? It's all the ones that people think about when you talk about solid tumor. The breast cancer, including triple negative breast, the ovarian cancers, mesothelioma, non-small cell lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer.
ERIC OSTERTAG: And if that's not a long enough list, there are actually many others.
ALEX PHILIPPIDIS: Great. And looking at that process, the fully allogeneic approach to Poseida-- first of all, you're on Close to the Edge. I'm Alex Philippidis of GEN with Eric Ostertag, CEO of Poseida Therapeutics. And that fully allogeneic approach, and I know you mentioned earlier, uses booster molecules. How does it make hundreds of doses from just a single manufacturing run?
ERIC OSTERTAG: Well, there's something that other people have coined in the allogeneic CAR T space called the allo tax, which means when you genetically modify yourself-- which you have to do because you can't just take one person's T cells and put them in somebody else's body-- there's actually two separate problems that occur. One is those T cells can attack that person, and that's called graft versus host disease. That could be potentially fatal. And then you have that person's T cells attacking the product.
ERIC OSTERTAG: That's not a safety issue, but that can shorten the duration of your cells. When you genetically modify a cell to get rid of that alloreactivity, you, generally speaking, make it a more exhausted, more differentiated, or mature product that doesn't work as well in the body. So that's where you get this idea of an allo tax. We don't see that because our genetic modification technologies work in these resting stem cells we get these cell products from donors that are typically younger, healthier.
ERIC OSTERTAG: They have higher percentage of these cells to start with. So we don't actually see an allo tax. In fact our product is better you might call it a allo tax credit, I guess. And then there's a second, I call it kind of dirty little secret in the space, which is when you do genetically modified to knock out the endogenous cell receptor-- which you have to do.
ERIC OSTERTAG: That's how you get rid of the graft versus host problem. When you do that you eliminate the ability to expand these cells, and that's a yield issue. So if you look at our competitors, allogeneic works. That's great. That's big news. But you don't get a lot of doses and the doses you do get are less potent. So the head of R&D at our company, Poseida, came up with a really brilliant solution.
ERIC OSTERTAG: His name is Devon Shedlock. And this is called the booster molecule, which functionally substitutes for that TCR, but only during manufacturing. So you put this, essentially, on the surface of the cell transiently. You can use the same reagents you would normally expand a product with and you do it in a way that maintains the stemness.
ERIC OSTERTAG: So right now in both the multiple myeloma clinical trial and the prostate trial we talked about, we're seeing remarkably good efficacy at very low dose, talking about 20 million cells, 50 million cells. So if you do the math at a 50 million cell dose with the amount of cells we can get from a healthy donor, you could actually get 500 to a thousand doses from a single manufacturing run.
ERIC OSTERTAG: So you can imagine that greatly reduces the cost. And I think there are two major hurdles for CAR T right now. One is toxicity. We already talked about how we're solving that with the stemness. And the second is cost. So if you make a fully off the shelf, fully allogeneic, low cost of manufacturing product like we are, I think you've solved those two problems, you've solved the accessibility issue.
ALEX PHILIPPIDIS: You mentioned just now challenges with CAR T. How similar or different are those challenges for gene therapy?
ERIC OSTERTAG: I think they're a bit different. I mean, on the one hand you do have immune reactions to deal with when you talk about an allogeneic CAR T, and you do have immune reactions to deal with, as we discussed earlier, with in vivo gene therapies. So yeah, they're shared in that sense. But there are other problems that are more inherent to in vivo gene therapy. Of course, technical hurdles like getting the DNA into the right cell and not other cells getting that DNA then integrated into the genome safely.
ERIC OSTERTAG: We think we've overcome those technological hurdles, but one really big advantage of our technology that isn't maybe so obvious is when you think about the standard gene therapies out there using AAV, it's a non integrating technology. It's transient. If you talk about the nanoparticle technologies delivering just RNA or just DNA, they're both transient. They don't integrate.
ERIC OSTERTAG: So you're looking at a therapy that has to be administered multiple times. In an adult with a slowly dividing liver, that might work for months to years. But in a pediatric or juvenile patient, which is where the majority of these diseases manifest, especially the more severe indications and the more severe patients within those indications, you can't treat that with those transient therapies because they have a rapidly dividing liver.
ERIC OSTERTAG: The nonintegrating therapies just get diluted out very, very quickly. So that's where piggyBac has this single cure capability. You put it in. Within 24 hours it will integrate that therapeutic transgene into the liver. And it doesn't matter if you look at the descendants of those liver cells two weeks later or two years later, or we think 20 years later.
ERIC OSTERTAG: They will all have high level stable expression of your therapeutic transgene. So that's a big key difference we've shown now with three different animal models of congenital disease we can get that single treatment cure. Now with the biodegradable nanoparticles, we do believe you're can redose. You might not need to, but we think can redose. Which is, again, a differentiator from the AAV therapies.
ERIC OSTERTAG: So again, I think this is why Takeda did the deal with us. They're looking to the future with nonviral gene therapies. They believe in functional cures, as do we. So I think the future for gene therapy is really bright because when we show proof of concept in these first couple of indications OTC, factor VIII, hemophilia A, there are dozens and dozens, maybe hundreds of other indications you could immediately treat using the same approach.
ALEX PHILIPPIDIS: And that redosing capability, how much is Poseida's answer to addressing the issues of high dosing that some other companies have encountered?
ERIC OSTERTAG: Well, if you think about AAV it's very difficult to redose and you have to, because of the transiency problem, dose at very high amounts. And at those titers you're getting sometimes fatal toxicities. I'm sure don't have to tell you it seems like every single week there's some problem with an AAV based company or a clinical hold with an AAV based clinical trial.
ERIC OSTERTAG: So first of all, simply by adding the piggyBac technology even to the older AAV technology, you can get the same effects but with several order of magnitude lower titer. So right there out of the gate you're eliminating a lot of these safety concerns with AAV. Now when you switch to nanoparticle, again, you can increase the cargo capacity. You don't have to worry about pre-existing immunity and you can redose.
ERIC OSTERTAG: So that's not true of every nanoparticle. Some companies have non-biodegradable nanoparticles and you'll get cumulative toxicity, so you can maybe redose a few times. We potentially could dose indefinitely, but of course, we're hoping you have to. That we can get a single dose and cure the patient, even the pediatric patients.
ALEX PHILIPPIDIS: Great. And looking ahead for Poseida, what's the company's current headcount and how much is that likely to grow in the coming year?
ERIC OSTERTAG: Well, right now we just passed 250 employees. We've been rapidly growing year on year every year for at least three years. In fact, there was a company-- I don't remember the name-- that ranks all companies in the world by a variety of metrics and supposedly they have artificial intelligence to do this. And by looking at all companies, all sectors, for several years in a row we've been one of the top 10 in San Diego for growth and one of the top 100 in the world for growth.
ERIC OSTERTAG: So I anticipate that rapid growth will continue, certainly with the Takeda partnership. Now we have more indications we're going to be working on, we're going to need more brilliant scientists and more space to achieve that.
ALEX PHILIPPIDIS: Mhm. Well, will that growth be likely in the San Diego area or will you look elsewhere?
ERIC OSTERTAG: Yeah. Our headquarters are in San Diego and we don't intend on moving the headquarters, so all of our research is also done in San Diego. There are some CROs or CMOs that do work for us outside of San Diego, but for the most part it's entirely San Diego based. Now one thing that the pandemic has taught us is that there are some people who can work remotely and so we have expanded to a number of other states where fully remote positions now are available.
ERIC OSTERTAG: And that's great because that might allow us to get people from Boston area, for example, that normally, for personal reasons, couldn't relocate to San Diego.
ALEX PHILIPPIDIS: And I know Poseida recently announced a series of leadership appointments. How much will growth center on building up leadership and how much in operations like R&D or administrative?
ERIC OSTERTAG: Well, we have a fantastic leadership team and because of that, these changes really were just part of longer term planning. These are internal promotions. Not a single one of those that we announced was an external hire. So we have some great people that we've been developing and not to say that as we grow, we, of course, will not be hiring externally also, but these changes that we just announced were planned and are just really things that were long term planning and also will help us manage the growth that we do expect after the Takeda deal.
ALEX PHILIPPIDIS: Mhm. And what else is next and what's Poseida looking forward to?
ERIC OSTERTAG: Well, it's a really bright future. There are definitely people who are alive today because of our drugs. We've got a gentleman in our BCMA101 clinical trial who's now 3.5 years out in a durable response. Now this guy when treated had failed everything. He couldn't get out of bed and probably was weeks from death. He's now surfing, he's biking, he's running in the mountains. He's probably more active than I am. So likewise we just announced a solid tumor patient that's now six months out doing really well.
ERIC OSTERTAG: So those are really fulfilling, but not every patient reacts that well. Not every patient has that kind of duration of response. So we're just going to continue to work hard to achieve our goal of these single treatment cures. That's why we say our tagline is the capacity to cure. We've proven that, but now we want to make that happen for more indications and more people.
ALEX PHILIPPIDIS: Great. And just like, that our time is drawing to a close for this episode of Close to the Edge. Thanks to our special guest Eric Ostertag, CEO of Poseida Therapeutics. I'm wishing you and the company all the best going forward
ERIC OSTERTAG: My pleasure. Thank you, Alex.
ALEX PHILIPPIDIS: Check out GEN Edge for other Close to the Edge interviews with outstanding chief executives, including Sujal Patel of Nautilus Biotechnology, John Evans of Beam Therapeutics, Daphne Zohar of PureTech Health, serial entrepreneur Nessan Bermingham and Ted Love of Global Blood Therapeutics. GEN Edge is where biotech gets down to business with exclusive in-depth reports from the GEN team. Please consider a free trial subscription.
ALEX PHILIPPIDIS: You can find GEN Edge on GEN's website, genengnews.com. Close to the Edge is produced by Bobby Grandone and Donny [? Budda. ?] I'm Alex Philippidis. Thanks so much for watching and goodbye for now. [MUSIC PLAYING]
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ALEX PHILIPPIDIS: Howdy, and thanks for taking the time to watch Close to the Edge, the new video series from GEN Edge where we invite chief executives and outstanding scientists from groundbreaking biotech and pharma companies to sit down with us to discuss their science technology and their business strategy. I'm Alex Philippidis, senior business editor with GEN, Genetic Engineering and Biotechnology News, the publication covering the biotech industry for 40 years.
ALEX PHILIPPIDIS: Close to the Edge is an offshoot of GEN Edge, our new premium subscription channel from GEN providing in-depth exclusive news, interviews, and analysis of key trends in the biotech industry coupled with a range of multimedia offerings, such as this one. More details of our free trial offer are at www.genengnews.com/genedge. All one word, G-E-N-E-D-G-E. On today's episode, episode nine, we welcome Eric Ostertag, an MD PhD who is CEO of Poseida Therapeutics.
ALEX PHILIPPIDIS: Poseida is a developer of curative cell and gene therapies based on its own proprietary gene engineering platform technologies, which we'll learn more about during today's episode. Those platforms recently attracted the interest of Takeda Pharmaceutical, which has committed up to $3.6 billion toward a collaboration with Poseida that we'll discuss a little later in this episode. Eric, welcome to Close to the Edge.
ERIC OSTERTAG: Hi. Thanks, Alex. Good to be here. Thanks for the invite.
ALEX PHILIPPIDIS: Sure. It's been an exciting few years for gene therapy as a whole. How do you assess the fields of cell and gene therapy these days?
ERIC OSTERTAG: Well, I think the fields have come a long way. I was the first graduate from the, at the time, brand new gene therapy program at University of Pennsylvania. That was 25 years ago when I started. So at that point gene therapy was really more science fiction and it's, at this point, actually resulting in some functional cures for both cancer and genetic diseases. So it's certainly come a long way and I think the next steps would be to get those cures extended to more diseases and more people.
ALEX PHILIPPIDIS: Now, at U of Penn gene therapy program. I understand you studied under Jim Wilson, who has been involved with us at Liebert over the years, was an editor of Human Gene Therapy Journal at some point. A pioneer in the field, for sure. What was that like working in his lab?
ERIC OSTERTAG: Yeah, no doubt he is a pioneer. Some people might call him a godfather of gene therapy. And I did work in his lab very early on. I ultimately did my PhD in another genetics pioneer named Haig Kazazian, but Jim's lab was very early in gene therapy work. Funny story. One of the very first things Jim did when I started in his lab was he sat me down in his office and said, OK, when I was doing my MD PhD, I was worried I couldn't finish fast enough because every problem in gene therapy was going to be solved.
ERIC OSTERTAG: And the point of the story was to give me comfort that I should just take my time and do a very solid PhD. And of course, here we are 25 years later and finally, we're at the doorstep of very large successes in gene cell therapy.
ALEX PHILIPPIDIS: Yeah. So how did you get interested in molecular biology to begin with then, and pursuing a career in the field?
ERIC OSTERTAG: You know, I always knew I wanted to be a scientist even from a very young age, probably early grade school. I'm very fascinated with science and I guess it was probably high school I learned about genetics. That was from my friend's father who happened to be my biology teacher and genetics really just blew me away. I wanted to do it.
ERIC OSTERTAG: I knew I loved it and I asked the question, and I'm sure others were at that time, if cancers and many congenital diseases have an underlying genetic component, why not fix it? Why not fix the underlying problem rather than give somebody a drug every day or every week for their life? So that's the concept behind gene therapy. And I then went to University of Wisconsin where I'd already been accepted into medical school out of high school.
ERIC OSTERTAG: I still had to do college, but I was given conditional acceptance. So I didn't really plan on going anywhere else, but as I progressed through my classes I realized that the new idea of gene therapy was taking off and my advanced genetics teacher told me I really needed to look at University of Pennsylvania. Of course, that's where Jim Wilson was. And so I did apply late in the cycle.
ERIC OSTERTAG: I also wrote to Michael Blades, who has an MD PhD and was also a very early clinical pioneer in gene therapy. And he told me, look, if you want to do gene therapy you really need an MD and a PhD. So everything kind of converged on University of Pennsylvania and that's where I did my MD PhD and then ultimately residency and fellowship also.
ALEX PHILIPPIDIS: All right. You mentioned a lifelong interest in science. Was there either a teacher or an event that got you interested in the broader field of science?
ERIC OSTERTAG: Well, my father is a psychologist. My mother's a NICU nurse, my sister became a NICU nurse. So really the family's been pretty heavily involved in the medical side of things. And even my grandmother got her PhD, which at the time I think was a bit unusual, and so I think that's been a big part of my family and my life for as long as I can remember.
ALEX PHILIPPIDIS: And check me. From U of Penn you went to a few companies from PhenoTec to Vindico NanoBioTechnology, then Transposagen, which you founded. How did you get around in your early career into companies? Because these look like startups just hearing about them or at least early stage, for sure.
ERIC OSTERTAG: Yeah. It was sort of a path I didn't intend on going down. I thought I'd be a physician scientist like I trained to be in academia. And I had a great academic project lined up that was working really well during my fellowship and I was waiting for a position at Penn in my department, which would have been transfusion medicine. They have a leading department there. That's where you would take cells out of the body, but possibly engineer them and put them back in.
ERIC OSTERTAG: That's really where CAR T or chimeric antigen receptor T cell therapy came out of. And it was a series of events where while I was waiting for the-- getting a little bit of background there. While I was waiting for the opportunity, my mentor was starting a company called PhenoTec to use nanoparticles-- well, at the time it actually wasn't nanoparticles, it was a method to do blood typing.
ERIC OSTERTAG: And I started looking at nanoparticles coming out of University of Pennsylvania as a possible solution. So I became increasingly involved with sort of running that company both from the science and a bit from the business side. And I was also trying to move this technology I was working on, which is called a transposon technology, forward, but the tech transfer office there wasn't licensing it. And out of my frustration I said, look, let's just start a company.
ERIC OSTERTAG: I can run it, I'll write some grants, and eventually I'll hand it off to another CEO. But that eventually never happened, and here I am. So PhenoTec we actually kind of evolved into a company I co-founded called Vindico and Vindico was ultimately purchased by Poseida. So the company I founded, other company, was Transposagen. That grew very large and we spun out Poseida from Transposagen.
ERIC OSTERTAG: So they're really all related. They're all related entities.
ALEX PHILIPPIDIS: Hmm. So that spin out of Poseida from Transposagen took place in 2015. How and why did Transposagen and spin out Poseida?
ERIC OSTERTAG: Well, as I mentioned, Transposagen was very early. This was early 2000s where gene therapy was pretty early stages. The goal of that company was human gene therapy and we had full legal name was Transposagen Biopharmaceuticals. But I would say the technologies, ours and others, weren't ready for the clinic at that point. They were developing.
ERIC OSTERTAG: As you know, there were some setbacks early on in the gene therapy space. So while we were developing these really powerful genetic engineering technologies, we sold what we had and that was these same tools as reagents, and we would also make cell lines and animal models. Now that reagent business became quite lucrative. It was supporting the business. And so by the time we did a deal with Janssen J&J in 2014 in the early CAR T space, that's when I decided we should really split the companies because the parent company was working on a reagent business.
ERIC OSTERTAG: There were other applications like agriculture that we were working on and human therapeutics is, of course, just a little bit of a different beast. So I thought it would be better to split those companies by field of use, and that's exactly what we did, with Poseida having all of the human therapeutics.
ALEX PHILIPPIDIS: Mhm. How did that spin out company come to be called Poseida?
ERIC OSTERTAG: Yes. It's an interesting story. I mentioned there were a lot of different applications of these powerful platform technologies-- gene delivery, gene editing, eventually the nanoparticle technologies-- and so I didn't think one company could do all of it. And so by splitting the companies by field, one company that spun out was focused on the genetic testing aspects and CRO aspects. And that was named Hera after the Greek goddess of heritability.
ERIC OSTERTAG: So I thought it would be fun to name the agriculture applications Dimitra after Demeter which was her sister, goddess of agriculture. And there is only one sister left, Hestia. And Hestia is the goddess of home and hearth. I didn't really think that was a good description for where we were going with Poseida. So I look to the brothers. Zeus was kind of taken already, I think, in biotech.
ERIC OSTERTAG: Hades didn't have the right connotation. So I named it Poseida after Poseidon, the only other brother.
ALEX PHILIPPIDIS: Hmm. That's great. Now you mentioned in those early years of gene therapy, the field had been struggling to overcome, and Jim Wilson has talked about this publicly, the Jesse Gelsinger death in 1999. And for many years investors shied away from gene therapy and companies didn't get as far as they have in more recent years. How did that affect your own startups and even early Poseida?
ERIC OSTERTAG: Yeah, absolutely. So the work I did in Jim's lab was before Jesse Gelsinger died, and then I moved to a more basic science lab project on these retrotransposons called LINE1 because I knew that they could be used both they and DNA transposons as a nonviral DNA delivery technology. The other half of Haig Kazazian's lab was a very much pioneer in gene therapy.
ERIC OSTERTAG: It was working on hemophilia factor VIII, which is ironically today one of our therapeutics in our pipeline. Also irony, by the way, he discovered active LINE1 transposons because they caused a mutation in a child with hemophilia and here we are 30 years later possibly being able to cure the disease with a different type of transposon. Anyway, that, I think, was a good experience for me. I think it was the right choice.
ERIC OSTERTAG: But as you said, the early technologies were viral based and the problem with viruses, although they've evolved for millions of years to be good at delivering DNA into human genomes, the human has been very good at evolving ways to prevent this. And part of that is the immune system. Some of the immune reaction can sometimes be problematic if not fatal, right? So even then 25 years ago in Jim's lab, I was working on hybrid viruses to try to get the best of all worlds, to get something that would integrate stable into the genome, thereby allowing potentially single treatment cures for genetic diseases but to eliminate the immune reaction.
ERIC OSTERTAG: And at the time the idea was, well, you just need to keep stripping proteins and genes out of a virus until the immune system can't recognize it as virus. It was about that time I had the idea, well, why not just build something that functions very much like a virus but isn't a virus? And there are two halves to that. One is a gene integrating system, and that's your DNA transposon which I spent my PhD working on, and the other half is a nanoparticle.
ERIC OSTERTAG: That would be substitute for the capsid, which gets the technology into a cell, and there you have it. It's functionally similar to a virus, but it has many advantages over viral technologies. And that's precisely what Poseida is focused on, nonviral DNA delivery.
ALEX PHILIPPIDIS: Mhm. And you mentioned advantages of these. How would you sum up those advantages in Poseida's approach?
ERIC OSTERTAG: Well, in terms of piggyBac, for example, this is a DNA transposon that can deliver potentially large, cargo large therapeutic transients. So it's at least 20 times larger than even some of the biggest viruses that have large cargo like lentivirus or gamma retrovirus, AAV, of course, which is a classic virus used in gene therapy, is even smaller. It's only 4.5 Kb. And it's a safer integration profile.
ERIC OSTERTAG: It's about 40% less intragenic than lentivirus. So we say it's nonmutagenic, it's nononcogenic, like some of the early gamma retroviruses, and it is easy to make. It's just GMP DNA and RNA versus GMP virus, which is time consuming, costly. So it's faster to clinic, lower cost, and it works really in every single cell type tested. That includes dividing cells, nondividing cells, you don't need DNA replication.
ERIC OSTERTAG: That has some huge advantages in CAR T, for example, because we can get into a desirable cell type that you really can't achieve with the viral technologies. So that's the half of the equation I talked about, getting the DNA integrated into the genome in a way that is very safe and that the body doesn't recognize as a virus. So the second half then would be to encapsulate that in something if you're doing in vivo gene therapy.
ERIC OSTERTAG: If it's outside the body or ex vivo you can just use what's called electroporation, of course. Now for in vivo, you would package that. And if you put that in a biodegradable nanoparticle, the advantages of a virus are, one, you don't see pre-existing immunity so there's not a portion of the population you can't treat. Number two, you don't create immunity. So you, first of all, can redose if you need to.
ERIC OSTERTAG: You also don't get these whopping immune reactions, so it's a much better safety profile and it's easier to manufacture, lower cost to manufacture. And to top it all off you have this cargo capacity advantage then. So it's really got the ideal characteristics you would want to potentially treat just about any genetic disease or any oncologic indication.
ALEX PHILIPPIDIS: Mhm. So then what are Poseida's disease focuses and how and why did the company come to focus on cancer and genetic disease?
ERIC OSTERTAG: Well, again, I mean, it's just as simple as the original idea that if all cancers have some sort of genetic component and congenital diseases have some sort of genetic component, why not fix those? So we developed what I think are best in class gene addition technology. That's piggyBac. We have, I believe, best in class gene editing technology. We call that Cas-CLOVER.
ERIC OSTERTAG: And we have some best in class gene delivery technology. That's the biodegradable nanoparticles. And you can kind of mix and match those in any way to do just about anything in gene therapy, either ex vivo or outside the body-- CAR T would be an example of that-- or in vivo. So we try to pick indications that really highlighted the advantages of our technology. So for example, in the CAR T space we started with a hematologic malignancy which was multiple myeloma.
ERIC OSTERTAG: A little bit harder than what people were working on at the time, the B cell leukemia and lymphomas. We recently then move to solid tumor with some great success treating prostate cancer and then in the gene therapy side, the in vivo gene therapy, we started with OTC which actually was the indication that Jesse Gelsinger had. We think we can do that safely, effectively, and we can actually treat the pediatric patient population, which you can't do with the more classic AAV approaches.
ERIC OSTERTAG: And so that was a great proof of concept. And then the next indication, which we did partner with Takeda, was hemophilia A. The transgene there is factor VIII, which is really large. You can't fit that in a standard AAV capsid, so that was a great way to showcase some of the advantages we just talked about of going to fully nanoparticle technology.
ALEX PHILIPPIDIS: And we'll definitely talk about the Takeda collaboration a little later, but I wanted to learn more about the Poseida approaches to overcoming primary limitations of current cell and gene therapeutic. You mentioned a nonviral piggyBac DNA modification system and Cas-CLOVER and there also are nanoparticle and AAV based gene delivery technologies. What determines which approach you wind up using?
ALEX PHILIPPIDIS: Is it disease specific or what?
ERIC OSTERTAG: It is somewhat disease specific and it's also I would call it therapeutic modality specific. So for example in the CAR T space, this is an ex vivo form of gene therapy, meaning you take the cells out of the body, you modify them, and you put them back in. Now in this case, it's T cells. What we've learned is that not all T cells are equal. So maybe not surprisingly, not all CAR T products will be equal.
ERIC OSTERTAG: It really depends on the type of cells that you get in the final product. Now this is a somewhat new concept because the cell type that we use is called TSCM, for stem cell memory T cell. That was only really described in humans less than 10 years ago and here we are six years ago already making CAR T products out of it. It's a desirable cell type because it's the true T stem cell.
ERIC OSTERTAG: This is your self-renewing, long lived, multipotent cell that gives rise to all your other T cells in your body like your CD4 positive helper cells, CD8 positive killer cells, your T regs, they all come from this cell. Normally the nongenetically modified version of this cell would last a lifetime. So if you get infected with the virus these are your memory cells that years from now, if you get reinfected, they'll immediately start killing the infected cells.
ERIC OSTERTAG: So great cell type to have for a CAR T product. The problem is, the viral technologies really don't get into this cell type because you have to activate cells to even get the viral infection. PiggyBac doesn't have that problem. It goes actually preferentially into these TSCM cells. So what we've seen now in the clinic when you make a high TSCM product is it's associated directly with best responses, the percent of TSCM in your product.
ERIC OSTERTAG: It gives you some remarkably long duration of response. It can give you a better safety profile. And most importantly, I think, is that it works in solid tumors. And that's kind of a complicated explanation for why that is, but we recently showed, I think, the best results ever for CAR T against a solid tumor indication where we had complete tumor elimination in at least one patient out to six months.
ALEX PHILIPPIDIS: If you could talk about that, that's something that the company had discussed pretty recently. Some positive results.
ERIC OSTERTAG: Right. So the drug was called-- or product candidate, I should say, was called PPSMA101. And this is a autologous CAR T, meaning individualized therapy for metastatic castrate resistant prostate cancer. As I'm sure you know, prostate cancer is very common in men. It is somewhat slow growing when it starts usually and has some treatments. But once it progresses to what's called castrate resistant, meaning it's failed anti-androgen therapies, it's a very aggressive disease with unfortunately short five year survival rates of 30% or less.
ERIC OSTERTAG: So huge unmet medical need here, large number of men who have this indication. And so what we did is made a CAR T that targeted a molecule called PSMA that's very specific to prostate cells. These men no longer have a prostate because it's been removed, so there are really no other cells in the body that express this PSMA, or at least at levels that are recognized by the drug.
ERIC OSTERTAG: And what that means is you don't have to worry about on target off tumor toxicities. We've seen very nice safety profile so far with this product. And because it's expressed at high levels on the prostate cancer cells, you can get very good targeted killing of those cells. And again, I think it's mostly because of the stemness of our product compared to others.
ERIC OSTERTAG: You actually get a strong and durable response. These cells are thought of more like a prodrug. They can graft in the bone marrow and then they can make wave after wave of the drug, your effector cells. So they kind of chip away at these tumors and we've definitely seen that in a number of patients now. More than half of our patients have had PSA, which is a biomarker for this disease decline.
ERIC OSTERTAG: About a third of patients have seen substantial declines of more than 50%, and a couple patients, including the one I mentioned, have very drastic declines shown by imaging with one patient showing at least, by imaging and PSA levels and even a bone marrow biopsy, evidence of complete tumor elimination.
ALEX PHILIPPIDIS: Wow. So what happens or where is that prostate cancer candidate now in development?
ERIC OSTERTAG: We're going to continue with the clinical trial. Obviously that's very promising, and that would involve increasing the dose level, that would involve trying some other strategies like maybe dividing a dose into multiple smaller doses, and we've also then made or are working on in our pipeline a fully allogeneic version of this. This would be something instead of making it from a patient with prostate cancer, we make it from a healthy donor and it's an off the shelf product.
ERIC OSTERTAG: We can make, we think, hundreds of doses from a single donor. So you can imagine that drops the cost of manufacturing quite a bit. We actually increase the stemness in these fully allogeneic products and that, we think, will increase the desirable attributes I just talked about, this efficacy, safety, the duration of response. All of that would then be in a fully allogeneic CAR T and we've already launched a couple of these.
ERIC OSTERTAG: One is for multiple myeloma and just received safe to proceed from the FDA a few weeks back. We also have a second one for pan solid tumor, meaning we think this could treat many different types of cancers, including lung cancer, breast cancer, ovarian cancer. It's called MUC1C-ALLO1, and that has an IND later this year. And then the prostate cancer one I talked about will be following those sometime either next year or the year after.
ALEX PHILIPPIDIS: OK. So these still have a ways to go in the clinic then.
ERIC OSTERTAG: Well, yeah. Some of these indications are because of the unmet medical need such that you can do a phase I, phase II clinical trial with potential accelerated approval. So it is shorter than some types of drugs, but of course, the clinical trial process is regulated by the FDA and rightfully so you have to prove safety first. So they do take usually several years.
ALEX PHILIPPIDIS: And also interested in the Cas-CLOVER site specific gene editing system you mentioned. A little bit on how that works and what sort of challenges in gene editing, and I'm thinking of off target edits, that this would attempt to avoid.
ERIC OSTERTAG: Exactly. Great question. And likewise we were very early in the gene editing space, so the company, parent company, had talked about Transposagen had an early version of a TALEN, which we called XTN. We also had a one from a different genus called ralstonia called RTN. So we had a lot of early experience with TALEN creation, TALEN design.
ERIC OSTERTAG: And we had some notable people on our scientific advisory board that are leaders in the gene editing space like Keith Joung and George Church. So we were really following these advances right as they were occurring and we had the opportunity to license the zinc finger nucleases. Actually, one of my friends who unfortunately passed away, Carlos Barbas, had a big hand in creating the zinc finger binding modules for those.
ERIC OSTERTAG: So we were aware of them. They were very expensive at the time and they did have some downsides. And as you know, the field started evolving very rapidly. So first there were the TALEN technology which we were in. Then there was, in addition to the zinc finger nucleases, the ability to make these fully dimeric, and that's where Cas-CLOVER came from. That eliminates some of the off target problems with the TALEN so we call that TAL-CLOVER.
ERIC OSTERTAG: And then after that, of course, CRISPR. Huge leap forward. Easy to use, easy design, low cost, has multiplexing ability, but it's a very sloppy enzyme. It creates a lot of unwanted off target mutations. So we kind of combined a couple of those ideas. We took a completely catalytic inactivated Cas9 protein from the Cas9 CRISPR system. So it still can use RNA to get you to specific places in the genome, it's a ribonucleic nucleoprotein DNA binding protein, and we then fused that to this very clean nucleus, which the scientific name is CLOV051.
ERIC OSTERTAG: We call it CLOVER. So instead of TAL-CLOVER where we fuse that to a TAL array, we now had it fused to this Cas9 protein. And that's where you get Cas-CLOVER. Cas-CLOVER we found was really ideal. It had the best of all worlds. The low cost multiplexing ability of the CRISPR system, but with this exquisitely specific enzyme fused to it. It will only cut DNA if two half sites are present at the exact same place at the exact same time in the genome.
ERIC OSTERTAG: Now this is different than a CRISPR Nickase, which can still go to other places in the genome and create nicks and breaks. This does not. So it's very clean and it doesn't have the off target problems with some of the other systems. So that's what we've been using for our fully allogeneic CAR T programs. And of course, we could eventually use that directly as a therapeutic and that is part of the Takeda collaboration.
ALEX PHILIPPIDIS: Mhm. On the Takeda collaboration, it includes up to six liver and hematopoietic stem cell directed indications, an option to add two additional programs through Takeda, potentially up to $3.6 billion. How did Poseida and Takeda get together?
ERIC OSTERTAG: Well, we've been talking with Takeda for a while, so they've been aware of our technologies. We meet at conferences like JP Morgan Health Care. And the talks just started taking off more recently because I think they were, like us, interested in achieving what they call functional cures. We say single treatment cures. Single treatment really could mean a series of a few treatments, but the idea is you give one or a few treatments and you're done for life.
ERIC OSTERTAG: That's the goal. So philosophically we're aligned. We're also aligned, I believe, in the idea that nonviral gene therapy is the future. So they're dabbling in other areas for sure, but I think they view that nonviral is the future of gene therapy and there aren't that many nonviral gene therapy companies, especially those that have all of the components we do.
ERIC OSTERTAG: The gene delivery, the gene editing, as well as the biodegradable nanoparticles. So they were interested, I think, in all of those applications and I think they're a great partner. They, as you know, purchased Shire. They really cemented their position as a leader, if not the leader, in rare diseases. So they have certain expertise in rare diseases, certain reagents maybe we don't have access to.
ERIC OSTERTAG: We've got the gene therapy tools, genetic engineering technologies they were interested in, so it's really a great match.
ALEX PHILIPPIDIS: Well, what do the companies plan to do through the collaboration?
ERIC OSTERTAG: Well, a couple things. You mentioned the multiple targets, multiple indications for both in vivo-- so this is all in vivo. Hematopoietic Stem Cell, meaning HSC, your true blood stem cell, can be used to treat a lot of different indications. But you could do that ex vivo like I talked about with CAR T and T cells. This was actually in vivo. So if you take the reagents, injecting them, they go find those HSCs in the body and genetically modify them.
ERIC OSTERTAG: And the other is the liver directive, which we had already been working on. We have still pipeline programs like OTC101 that are not part of this collaboration, but then we have some new ones that they can choose. And it also is a research collaboration, so we're continuing to develop our programs. We talked about piggyBac, we talked about Cas-CLOVER, we talked about the biodegradable nanoparticles, but there are some really cool things we're working on like a site specific version of the transposes site specific piggyBac, and of course, they're very interested in that also.
ALEX PHILIPPIDIS: Sure. , Now does this collaboration signal a change in pesetas pipeline approach toward more partnered programs? I know up till now a lot of the programs have been developed wholly by Poseida.
ERIC OSTERTAG: Well, we were in what I'd call stealth mode right up until our IPO a little over a year ago now, and I think it was right after that that people became aware of how broad our technologies were and how many different things we could do. We had a 4 and 1/2 hour R&D day and that triggered a lot of incoming interest from pharma companies, including Takeda as one example. And yes, that was intentional on our part to realize that, hey, these technologies are so broad.
ERIC OSTERTAG: You could do just about anything you can think of with advantages in either ex vivo or in vivo gene therapy, but a single company can't do it all and can't do it for every indication. So this was intentional to start partnering. And another thing we like about the Takeda deal is that didn't give up a lot. We do have our hemophilia A program which was in our pipeline going into that, but most of this is for indications that were not in our pipeline.
ERIC OSTERTAG: And I think we can do a lot of additional collaborations both on the cell therapy side and the gene therapy side that are similar to that type of value creating deal.
ALEX PHILIPPIDIS: Among the programs still wholly owned-- and we talked about this earlier-- was the prostate cancer program. Now that program began a year ago with a bit of a hitch when the FDA imposed a clinical hold after a patient had died of liver failure after developing symptoms consistent with macrophage activation syndrome, which according to the company, was exacerbated by noncompliance by the patient. And that hold was lifted three months later.
ALEX PHILIPPIDIS: Poseida agreed to implement protocol amendments and what were some of those changes?
ERIC OSTERTAG: Yeah. So first of all, there was a patient, one of the earlier patients in the clinical trial, that unfortunately had SAE. They came in late with acute liver failure and we were not able to or the physicians were not able to save that patient. We do know there was a significant noncompliance, meaning they skipped several important follow up appointments because we were able to dose fully outpatient given the safety profile of our BCMA101 program.
ERIC OSTERTAG: We've just over 100 patients there with very low rates of CRS. We've never seen a grade 3 or higher CRS, never had a patient even need to go to the ICU. So uniquely in this space, we could do outpatient dosing. We started doing that with the prostate cancer trial. So what was unfortunate about that in a really tragic way was we now know the cells were actually expanding and when we look at the other patients in the trial, that patient not only could have been likely saved because of the easily treatable side effects that we now see rarely in other patients, but the cells were expanding and in all likelihood could have received a lot of benefit from that.
ERIC OSTERTAG: So we did make our own recommendations to the FDA and those included trying to solve this noncompliance issue by hospitalizing patients for the first 10 to 14 days after treatment so they could be more closely monitored. The same tests that we were doing would have picked this up and in fact, did. It just was unfortunate that the patient came in too late. So we increased the frequency of some of the testing. There was already a built in mechanism to de-escalate to a lower dose, which we did.
ERIC OSTERTAG: So we recommended all this to the FDA. They had not one single additional change that they asked us to do. It was one of the shortest clinical holds I think possible. It was actually just a tad over two months. And I haven't really seen any hiccups since then. So we did release some data as part of that was safety. We only saw three additional CRS, no grade 3 or higher, and easily treatable with standard therapies like tocilizumab.
ALEX PHILIPPIDIS: So some encouraging data reported in August. When's the next update expected in that study?
ERIC OSTERTAG: Next update we've said publicly will be in the first half of next year and we haven't said the exact meeting, but it would likely either be ASCO GU in February or ASCO the parent meeting a little bit later in the year.
ALEX PHILIPPIDIS: Mhm. And on CAR T, I know Poseida has likened its CAR T cell therapy to an ex vivo form of gene therapy. How so?
ERIC OSTERTAG: Well, it really is. Right? We talked about this, but ex vivo gene therapy is take a cell out of the body, in this case it's a T cell genetically, modify it-- I like to say educate it to kill the cancer cells-- and then you put it back in the body. So that's definition of classic ex vivo gene therapy. We talked about how ours is different. It's nonviral.
ERIC OSTERTAG: That allows us to get these high TSCM cells and nobody else can do that. And I think what it highlights though is that we can use these same technologies, the gene addition and the gene editing we talked about now, in other cell types. So we've shown that actually gene editing for hematopoietic stem cells, we've shown for iPSCs. Both of those were at our research day.
ERIC OSTERTAG: And another thing we have that I don't think a lot of people were aware of is we've made a lot of progress with the CAR NK program. So that's an example where we would probably partner that. It can be used in different ways as a sort of semi allogeneic cellular approach for cancers, and that's something that we will not likely pursue as a pipeline product but we could certainly partner it.
ALEX PHILIPPIDIS: For sure. And on the CAR T front, companies reported plans to file two INDs for the multiple myeloma and the solid tumor indication programs. How far down the road are those? Would those be next year or further down?
ERIC OSTERTAG: No, these are first of all fully allogeneic. We have very strong confidence in our fully allogeneic program now. And the fully allogeneic cells we've shown in very predictive animal models work even better than the auto version, which is not typically the case for our competitors but I think, again, the stemness is important to that. We can make hundreds of doses through something called the booster molecule.
ERIC OSTERTAG: So that gives us a huge advantage in manufacturing costs. So the first IND you referred to actually already was filed this year and already was given safe to proceed from the FDA, so in the very short near term we'll start dosing our first patients. And then the second fully allogeneic IND that you referred to is also this year and that is for a target called MUC1c.
ERIC OSTERTAG: I referred to this briefly previously, but it's a, we think, pan solid tumor target, meaning just about any epithelial derived cancer could potentially be treated with this CAR product. And when you say, well, what's an epithelial derived cancer? It's all the ones that people think about when you talk about solid tumor. The breast cancer, including triple negative breast, the ovarian cancers, mesothelioma, non-small cell lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer.
ERIC OSTERTAG: And if that's not a long enough list, there are actually many others.
ALEX PHILIPPIDIS: Great. And looking at that process, the fully allogeneic approach to Poseida-- first of all, you're on Close to the Edge. I'm Alex Philippidis of GEN with Eric Ostertag, CEO of Poseida Therapeutics. And that fully allogeneic approach, and I know you mentioned earlier, uses booster molecules. How does it make hundreds of doses from just a single manufacturing run?
ERIC OSTERTAG: Well, there's something that other people have coined in the allogeneic CAR T space called the allo tax, which means when you genetically modify yourself-- which you have to do because you can't just take one person's T cells and put them in somebody else's body-- there's actually two separate problems that occur. One is those T cells can attack that person, and that's called graft versus host disease. That could be potentially fatal. And then you have that person's T cells attacking the product.
ERIC OSTERTAG: That's not a safety issue, but that can shorten the duration of your cells. When you genetically modify a cell to get rid of that alloreactivity, you, generally speaking, make it a more exhausted, more differentiated, or mature product that doesn't work as well in the body. So that's where you get this idea of an allo tax. We don't see that because our genetic modification technologies work in these resting stem cells we get these cell products from donors that are typically younger, healthier.
ERIC OSTERTAG: They have higher percentage of these cells to start with. So we don't actually see an allo tax. In fact our product is better you might call it a allo tax credit, I guess. And then there's a second, I call it kind of dirty little secret in the space, which is when you do genetically modified to knock out the endogenous cell receptor-- which you have to do.
ERIC OSTERTAG: That's how you get rid of the graft versus host problem. When you do that you eliminate the ability to expand these cells, and that's a yield issue. So if you look at our competitors, allogeneic works. That's great. That's big news. But you don't get a lot of doses and the doses you do get are less potent. So the head of R&D at our company, Poseida, came up with a really brilliant solution.
ERIC OSTERTAG: His name is Devon Shedlock. And this is called the booster molecule, which functionally substitutes for that TCR, but only during manufacturing. So you put this, essentially, on the surface of the cell transiently. You can use the same reagents you would normally expand a product with and you do it in a way that maintains the stemness.
ERIC OSTERTAG: So right now in both the multiple myeloma clinical trial and the prostate trial we talked about, we're seeing remarkably good efficacy at very low dose, talking about 20 million cells, 50 million cells. So if you do the math at a 50 million cell dose with the amount of cells we can get from a healthy donor, you could actually get 500 to a thousand doses from a single manufacturing run.
ERIC OSTERTAG: So you can imagine that greatly reduces the cost. And I think there are two major hurdles for CAR T right now. One is toxicity. We already talked about how we're solving that with the stemness. And the second is cost. So if you make a fully off the shelf, fully allogeneic, low cost of manufacturing product like we are, I think you've solved those two problems, you've solved the accessibility issue.
ALEX PHILIPPIDIS: You mentioned just now challenges with CAR T. How similar or different are those challenges for gene therapy?
ERIC OSTERTAG: I think they're a bit different. I mean, on the one hand you do have immune reactions to deal with when you talk about an allogeneic CAR T, and you do have immune reactions to deal with, as we discussed earlier, with in vivo gene therapies. So yeah, they're shared in that sense. But there are other problems that are more inherent to in vivo gene therapy. Of course, technical hurdles like getting the DNA into the right cell and not other cells getting that DNA then integrated into the genome safely.
ERIC OSTERTAG: We think we've overcome those technological hurdles, but one really big advantage of our technology that isn't maybe so obvious is when you think about the standard gene therapies out there using AAV, it's a non integrating technology. It's transient. If you talk about the nanoparticle technologies delivering just RNA or just DNA, they're both transient. They don't integrate.
ERIC OSTERTAG: So you're looking at a therapy that has to be administered multiple times. In an adult with a slowly dividing liver, that might work for months to years. But in a pediatric or juvenile patient, which is where the majority of these diseases manifest, especially the more severe indications and the more severe patients within those indications, you can't treat that with those transient therapies because they have a rapidly dividing liver.
ERIC OSTERTAG: The nonintegrating therapies just get diluted out very, very quickly. So that's where piggyBac has this single cure capability. You put it in. Within 24 hours it will integrate that therapeutic transgene into the liver. And it doesn't matter if you look at the descendants of those liver cells two weeks later or two years later, or we think 20 years later.
ERIC OSTERTAG: They will all have high level stable expression of your therapeutic transgene. So that's a big key difference we've shown now with three different animal models of congenital disease we can get that single treatment cure. Now with the biodegradable nanoparticles, we do believe you're can redose. You might not need to, but we think can redose. Which is, again, a differentiator from the AAV therapies.
ERIC OSTERTAG: So again, I think this is why Takeda did the deal with us. They're looking to the future with nonviral gene therapies. They believe in functional cures, as do we. So I think the future for gene therapy is really bright because when we show proof of concept in these first couple of indications OTC, factor VIII, hemophilia A, there are dozens and dozens, maybe hundreds of other indications you could immediately treat using the same approach.
ALEX PHILIPPIDIS: And that redosing capability, how much is Poseida's answer to addressing the issues of high dosing that some other companies have encountered?
ERIC OSTERTAG: Well, if you think about AAV it's very difficult to redose and you have to, because of the transiency problem, dose at very high amounts. And at those titers you're getting sometimes fatal toxicities. I'm sure don't have to tell you it seems like every single week there's some problem with an AAV based company or a clinical hold with an AAV based clinical trial.
ERIC OSTERTAG: So first of all, simply by adding the piggyBac technology even to the older AAV technology, you can get the same effects but with several order of magnitude lower titer. So right there out of the gate you're eliminating a lot of these safety concerns with AAV. Now when you switch to nanoparticle, again, you can increase the cargo capacity. You don't have to worry about pre-existing immunity and you can redose.
ERIC OSTERTAG: So that's not true of every nanoparticle. Some companies have non-biodegradable nanoparticles and you'll get cumulative toxicity, so you can maybe redose a few times. We potentially could dose indefinitely, but of course, we're hoping you have to. That we can get a single dose and cure the patient, even the pediatric patients.
ALEX PHILIPPIDIS: Great. And looking ahead for Poseida, what's the company's current headcount and how much is that likely to grow in the coming year?
ERIC OSTERTAG: Well, right now we just passed 250 employees. We've been rapidly growing year on year every year for at least three years. In fact, there was a company-- I don't remember the name-- that ranks all companies in the world by a variety of metrics and supposedly they have artificial intelligence to do this. And by looking at all companies, all sectors, for several years in a row we've been one of the top 10 in San Diego for growth and one of the top 100 in the world for growth.
ERIC OSTERTAG: So I anticipate that rapid growth will continue, certainly with the Takeda partnership. Now we have more indications we're going to be working on, we're going to need more brilliant scientists and more space to achieve that.
ALEX PHILIPPIDIS: Mhm. Well, will that growth be likely in the San Diego area or will you look elsewhere?
ERIC OSTERTAG: Yeah. Our headquarters are in San Diego and we don't intend on moving the headquarters, so all of our research is also done in San Diego. There are some CROs or CMOs that do work for us outside of San Diego, but for the most part it's entirely San Diego based. Now one thing that the pandemic has taught us is that there are some people who can work remotely and so we have expanded to a number of other states where fully remote positions now are available.
ERIC OSTERTAG: And that's great because that might allow us to get people from Boston area, for example, that normally, for personal reasons, couldn't relocate to San Diego.
ALEX PHILIPPIDIS: And I know Poseida recently announced a series of leadership appointments. How much will growth center on building up leadership and how much in operations like R&D or administrative?
ERIC OSTERTAG: Well, we have a fantastic leadership team and because of that, these changes really were just part of longer term planning. These are internal promotions. Not a single one of those that we announced was an external hire. So we have some great people that we've been developing and not to say that as we grow, we, of course, will not be hiring externally also, but these changes that we just announced were planned and are just really things that were long term planning and also will help us manage the growth that we do expect after the Takeda deal.
ALEX PHILIPPIDIS: Mhm. And what else is next and what's Poseida looking forward to?
ERIC OSTERTAG: Well, it's a really bright future. There are definitely people who are alive today because of our drugs. We've got a gentleman in our BCMA101 clinical trial who's now 3.5 years out in a durable response. Now this guy when treated had failed everything. He couldn't get out of bed and probably was weeks from death. He's now surfing, he's biking, he's running in the mountains. He's probably more active than I am. So likewise we just announced a solid tumor patient that's now six months out doing really well.
ERIC OSTERTAG: So those are really fulfilling, but not every patient reacts that well. Not every patient has that kind of duration of response. So we're just going to continue to work hard to achieve our goal of these single treatment cures. That's why we say our tagline is the capacity to cure. We've proven that, but now we want to make that happen for more indications and more people.
ALEX PHILIPPIDIS: Great. And just like, that our time is drawing to a close for this episode of Close to the Edge. Thanks to our special guest Eric Ostertag, CEO of Poseida Therapeutics. I'm wishing you and the company all the best going forward
ERIC OSTERTAG: My pleasure. Thank you, Alex.
ALEX PHILIPPIDIS: Check out GEN Edge for other Close to the Edge interviews with outstanding chief executives, including Sujal Patel of Nautilus Biotechnology, John Evans of Beam Therapeutics, Daphne Zohar of PureTech Health, serial entrepreneur Nessan Bermingham and Ted Love of Global Blood Therapeutics. GEN Edge is where biotech gets down to business with exclusive in-depth reports from the GEN team. Please consider a free trial subscription.
ALEX PHILIPPIDIS: You can find GEN Edge on GEN's website, genengnews.com. Close to the Edge is produced by Bobby Grandone and Donny [? Budda. ?] I'm Alex Philippidis. Thanks so much for watching and goodbye for now. [MUSIC PLAYING]
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