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The Bioverge Podcast: Advancing a Pipeline of Off-The-Shelf Cell Therapies

Brian Culley, CEO of Lineage Cell Therapeutics, sits down with Neil to discuss his company’s efforts to develop off-the-shelf cell therapies to treat degenerative retinal disease, spinal cord injury, and cancer.

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Brian Culley, CEO of Lineage Cell Therapeutics, sits down with Neil to discuss his company’s efforts to develop off-the-shelf cell therapies to treat degenerative retinal disease, spinal cord injury, and cancer.

Available on SoundCloud, here.

Available on iTunes, here.

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Full Transcript


Danny Levine (Producer)
Neil, we've got Brian Culley on the show today. Who's Brian?


Neil Littman (Host)
Brian is the chief executive officer of Lineage Cell Therapeutics, which is a publicly traded cell therapy company. Brian has a long history in the cell therapy field before lineage. He was the CEO of Artemis therapeutics before Artemis. He was the CEO of mast therapeutics. Really excited to have Brian on the show, continuing in our series, doing a deep dive into the regenerative medicine and cell therapy space.


Danny Levine (Producer)
Cell therapies have been costly in part because of the personalized nature of most of these therapies, lineage is developing off the shelf therapies. What's the potential for expanding the market with an off the shelf therapy?


Neil Littman (Host)
Well, the obvious implications are number one, easier to manufacture number two, obviously cogs or the cost to manufacturer these therapies. As opposed to the autologous therapies, cell therapies, which are dry from an individual patient, those cells are removed from a patient they're somehow genetically altered and then they're reinfused into the patient, right? That is a very time intensive and costly process. It, it is and will remain, I think great for certain indications. I think as we think about expanding the use of cell therapies more broadly, there's no doubt that there's a trend toward allogeneic or off the shelf cell therapies for, a variety of reasons, largely around the cost to produce them in terms of manufacturing. There also be easier to deliver as well in terms of supply chain and logistics. Lineage is particularly focused on off the shell therapies off the self cell therapies.


Danny Levine (Producer)
What are you hoping to hear from Brian today?


Neil Littman (Host)
Yeah. I want to dive into about their programs. Lineage has a lead program called op Regene, which is in the clinic for the drive version of AMD or age related macular degeneration. Love to hear about how those cells actually work. How do they function? What is the mechanism of action? Do they in graph? Do they only work by the pair akin or trophic effect? I'm particularly interested to hear about their other program OPC one, which is a treatment in the clinic for spinal cord injury. That is a program that I know quite a bit about. It was originally developed by a company by the name of Giran. That was one that was funded by the California Institute for regenerative medicine, as the listeners, no doubt know a place that I worked for many years. It was actually the very first embryonic drive stem cell that received an ind from the FDA and went into human clinical trial.


Neil Littman (Host)
That program in particular has a long history behind it. It's really interesting to see, that it's in the hands of lineage now. I really would love to hear an update about what they're doing with it.


Danny Levine (Producer)
Well, if you're all set,


Neil Littman (Host)
Let's do it. Brian, thank you so much for joining us on the show today. I'm incredibly excited to have you with us today.


Brian Culley (Guest)
Hey Neil, thanks very much. It is my pleasure to be here with you.


Neil Littman (Host)
I know you are the CEO of Lineage Cell Therapeutics, which is a publicly traded company. I will just give you a moment to go through some legal disclaimers and the safe Harbor.


Brian Culley (Guest)
Oh, thanks Neil. Yeah, folks can learn more about our risk factors through our public filings available@scc.gov because I may be making some forward looking statements today.


Neil Littman (Host)
Excellent. Well, now that's out of the way today, we are going to be talking about Lineage Cell Therapeutics. We're going to talk a bit about your pipeline. In general, I'm really excited to dive into the potential for cell therapies in general, to address unmet medical needs. Age-related degenerative diseases, other serious conditions as well. Before we do that though, Brian, I would love to get your perspective on where you think we are in terms of the evolution of cell therapies in the field in general.


Brian Culley (Guest)
Yeah. I'd be happy to stay that nail. I mean, I think that we're in version 2.0, and I say that because with a lot of new and emerging technologies and you think about the life cycle of a breakthrough technologies, oftentimes the excitement exceeds the reality in the early days. I think that was the case for self-therapy. Now, say 10 years on, we actually, as an industry have developed a lot of the tools that we didn't have available 10 years ago to deliver on those promises. What you see now is a realization or a maturation of self therapy of cell therapy. In connection with that, I think we're going to start seeing that accelerated growth that often accompanies new technologies. It's a really wonderful time to be involved in this field.


Neil Littman (Host)
Brian, can you talk about some of the specifics around what you feel make cell therapies particularly compelling when it comes to using them as a novel therapeutic?


Brian Culley (Guest)
Yeah. Th there are a couple of things that I think cell therapy might be able to do, which is beyond the reach of small molecules or antibodies, the traditional pharmacologic interventions of the field. That's because in some conditions, in some diseases and other conditions, the things that have gone wrong in the body are just so out of control that it's hard to imagine that just a single small molecule, no matter how potent and how powerful is really going to get the job done. If you have a disease for which a single problem can be pinpointed and a pill can be developed, that contains an active ingredient that addresses that one problem. That's wonderful, but there are a lot of conditions out there with severe unmet needs, for which the magnitude of the problem is so large where the entire cell is basically broken. I think that's where transplant medicine now, IE, using a whole cells transplanted in the body to restore activity or to repair function.


Brian Culley (Guest)
I think that's where cell therapy is really going to get its best foothold and then be able to build from there.


Neil Littman (Host)
Yeah. Brian, I think there's a lot to double click on in terms of what you just said. Obviously this is a relatively novel field in terms of, these types of cell therapies, heading the commercial market, being available to patients, there's a whole host of challenges that come along with that as well. What do you think are some of the major challenges that face the production delivery of cell therapies?


Brian Culley (Guest)
Well, some of the challenges that were originally identified in the early days, I think were the right ones. These are matters of things like scale. How do you, how do you manufacture huge numbers of cells, which is far more difficult than manufacturing, huge amounts of a small molecule purity and reproducibility are also important considerations, at the foundation of the scientific processes, you want to reduce variability. You want to be able to make the same material every time. Well, that's really hard with cells. I mean, even the cells that grow in the center of a plate behave differently than the cells, which grow on the periphery of a plate. There are a lot of challenges, but the industry has done a nice job chipping away at them in order to have today much more rigorous and defensible product candidates than some of the early and perhaps overly ambitious endeavors when cell therapy was first getting underway.


Neil Littman (Host)
Yeah. I think that's a really good point. I think that's a nice segue. I want to dive into some of the nuances of cell therapy. I, I know the field is evolving rapidly. The first iteration of a lot of cell therapies were autologous therapies, right? Where a patient cells have been removed, altered, and then are reinfused into the patient. I know at lineage, you are focused on developing off the shelf cell therapies or Alad allogeneic therapies. Could you talk about the differences between both of those maybe compare and contrast in terms of the implications from a cost perspective, a manufacturing point of view, how they may better or worse for the patient at the end of the day?


Brian Culley (Guest)
Yeah, of course we only work as you correctly said on allogeneic or off the shelf. We have a single fell line which can be scaled up to tremendous number. We can manufacture billions upon billions of the same kind of cell type. We have the benefit, not only of being able to drive down the cost of manufacturing because we can scale these cells essentially endlessly, but also we use the same material. In fact, the same cells that we're using in the clinic today, they're derived from a line that's more than 20 years old. Over 20 years it's been extensively characterized. It's very well understood. And it's the same material. Some of the other approaches that are out there may require you to obtain new material and develop new cell lines, or maybe as you said, harvest cells from a patient, expand them a number, and then either treat that one patient, or maybe you can expand it where you could treat tens or hundreds or even a couple of thousand patients.


Brian Culley (Guest)
But then what happens? You, you have to go back and harvest material again. Now you have a different donor with a different genome. And so you have different material. We are really pursuing what we think is the ultimate end of cell therapy, which are allogeneic off the shelf approaches because you just can't compete with the economic advantages of scaling. I have said sometimes that if you wanted to manufacture a billion pizzas, that you need to come up with many tons of peas and many, tons of pepperoni. If you want to manufacture billions and billions of cells, they're doing the work for you, right. They can replicate and divide. You just need to feed them the media. The ability to drive down costs by increasing the scale production of cells, which will self-replicate and retain their original identity, that's really powerful. We do that with a plurry potent cell line.


Brian Culley (Guest)
What's really special here to just be more technical for a moment is that the cell lines we use do not have a Hayflick limit. The Hayflick limit is the number of times you can passage or replicate cells before they accumulate so many mutations that they will replicate any further. If you take normal human adult cells and you replicate them in the laboratory environment, you might only divide them 20, 30, or 40 times, and you're done. You just can't squeeze out any more material, but with Clery potent cell lines, like the ones which we use, you can essentially replicate them for ever. That's where we get that power of the scale by being an off the shelf and allogeneic. I will say that autologous approaches where you start with a patient or customized approaches patient-specific specific approaches, they probably will have some application in certain settings because you never even have to consider fears of rejection.


Brian Culley (Guest)
We operate in the eye and in the spinal cord where those fears are greatly reduced. I think that overall there are going to be optimized solutions in these different categories. Broadly speaking, I think allogeneic just really has a leg up by virtue of the ability to scale and make it much more affordable and having consistent material every single time in every single dose.


Neil Littman (Host)
Brenda, I want to pick up on a thread that you had mentioned. Cause I think this is really interesting and that's the cell lines. I, if I'm not mistaken that the cell lines have a pretty interesting history behind them, could you talk about the origin of the cell lines that you're using today to develop therapies from?


Brian Culley (Guest)
Yeah, we have a cell line and it's, it really is kind of an amazing story. There was a couple 30 years ago that wanted to conceive a child. They couldn't do it naturally. They pursued an in vitro fertilization process, which means they created probably 10 or 12 embryos. This is something that's happening in the millions every year. So, several decades ago they were doing the same thing, but you don't implant 10 embryos into a person. You just implant a couple. If the couple is successful, as this couple was in conceiving a child, they had these additional they're called blast assists that are about six to seven days post fertilization. They remain in the freezer for, in this case five years. And then the couple is contacted. What do you want us to do with this material? We were not going to store it anymore. These are blastocysts, which are going to be discarded.


Brian Culley (Guest)
So they become medical waste. What was fortunate here is that a research scientist was able to get in contact with the owners of that material and, preserve it, save it scrapes six or seven cells off of it and establish a new cell line, which as I described in the last question has become a reproducible line that was expanded probably many billions of billions of times now. It's, it's really been an incredible journey of donating this material and then starting something that might be able to help millions of people preserve their vision was started by a cell line that was established just by scraping six or seven cells off of blast Jula from 30 years ago. It really has been quite a journey for this cell line to get to where it is today.


Neil Littman (Host)
Yeah. And it really is incredible. Why don't we dive in there and talk about your lead program up Regene which is for dry age-related macular degeneration with geographic atrophy. Could you talk about the disease, dry AMD? How does it manifest itself and how does it progress?


Brian Culley (Guest)
Yes. Dry AMD is it's a horrible disease. It's typically associated with aging. What occurs is that the RPE cells, so the specialized retina cells that support cells that are required for revision, they begin to die off. They, they age and they die off and as they die off, they are absent from, they're not replaced. They become absent from areas that are important for your ability to have central vision. We all are familiar with central vision and peripheral vision, but what happens is you first start to develop of waviness and then some black smudge genus and you're losing your central vision. You can't see it, can't see your phone. You can't see the faces of the people you're talking to. Over time it just gets worse and worse as these cells keep dying off and eventually you can become legally blind and then completely blind. This is happening to about 2 million people in the United States right now.


Brian Culley (Guest)
There's no thing to treat them there. There have been attempts to develop therapeutic interventions, but no one has been able to find a way to slow or stop this disease. Our approach, which is quite novel is to manufacture brand new retina cells. We can manufacture them literally 5 billion at a time in a three liter bioreactor. We can put about a hundred thousand of those cells into the eye to replace the ones that have died off and in doing so by putting in that new layer of cells, we're looking to have them functionally active and be able to protect against further degradation and in the data that we've collected today, it also appears that we are able to bring some vision back to these individuals. It really is quite an exciting area because it's a huge unmet need, but there's nothing approved. It really is open space for us.


Neil Littman (Host)
It's quite extraordinary. I want to just go back to the condition itself. There's the drivers of AMD, which as you point out has no available treatment options today. There's also another version of AMD or wet AMD, which if I'm not mistaken, does have some available treatment options today. Could, could you maybe just spend a minute and talk about the difference between the dry form and the wet form of AMD and why maybe one has treatment options today, whereas the drivers and doesn't.


Brian Culley (Guest)
Yeah, of course. I mean, it's so illustrative of why cell therapy is suitable in a setting of dry EMT. If we go to wet AMD, we understand we as an industry, understand molecularly what is going wrong? There's a specific pathway, which is leading to the, the leakiness of blood vessels, which causes what they call wet AMD. We have drugs actually borrowed from the oncology world. We have treatments that are approved to treat wet AMD because we know what's broken. If what's broken, what part you can get to fix. So those parts have been really successful. The commercially, the wet AMD drugs sell more than $10 billion a year. Meanwhile, dry AMD is poorly understood. We don't know exactly what is broken in the setting of dry AMD. People have tried to develop drugs, but they're kind of, going at it blindly to not intentionally make a poem there.


Brian Culley (Guest)
What we have is we have eight to nine times more people suffering from dry AMD, but yet we haven't found anything to intervene and be approvable by the FDA because we just don't know what's wrong. By the time you get to a cell dying off, probably there's thousands of things going wrong. That's why our view is if you can just manufacture a whole new retina cell, you might be able to slow this disease because you don't have to fret about trying to figure out which pathway is involved and whether it's clinically relevant or up-regulated or down-regulated or anything else. I don't know what's wrong in those cells. I'm going to just get you some brand new ones and you should be good to go.


Neil Littman (Host)
Let's talk about that for a minute. And, at the risk of getting too in the weeds and too geeky here, I do want to talk about op region and the mechanism of action. It sounds like as you just described that there may be a couple of different MOS, but one certainly seems to be that the cells actually in graft and then actually help reconstitute the, the vision and the functioning of the cells that have been damaged. Could you, could you talk about that? I know a lot of cell therapies for example, are injected and then they operate by the Peregrine effect, for example, and get washed away in this. I was never in graft. Could you just talk about, do yourselves and graft and also work via other mechanisms? If they do, it sounds like they're doing graph D have you measured the duration of that engraftment maybe, and maybe just help our listeners understand a little about the MOA and how these cells actually act once they're inside the eye.


Brian Culley (Guest)
Yeah, we ascribed to the idea that what we're doing is cell transplant. You really need to physically be placing the cells in the right place in order to get the effect. That's not to say that a Peregrine or trophic effects aren't beneficial. We, we do think that there probably are things that our cells do, which improve the micro for the immediate environment that are just secreted from the cells. In fact, we have released criteria to ensure that we have certain molecules that are being secreted from the atypical and basal sides of the cells, which we manufacturer, but are, are operating, ideal here is that's not enough. There may be a benefit from, happy molecules being secreted out of transplanted material. We think that really the effect is driven more profoundly by the actual introduction transplant replacement of cells and in Grafman. So, yes, we have seen that none of the patients that we've put the cells in have rejected the cells, and we have from the earliest patient who was treated now more than five years of data of showing that the cells are stable and grafted without being rejected.


Brian Culley (Guest)
That's quite exciting because that was one of the early fears to go back to the beginning of the call. The people thought, oh, you're going to put foreign material in is going to be rejected. We haven't seen that. In fact, we've reduced the immunosuppressive regimen from a year down to just 90 days. More recently, we actually treated someone who didn't even get a full course of immunosuppression and still maintained a stable graph. What we're seeing clinically is that our cells are able to be delivered to the right place. They can arrange into a monolayer, which is what they prefer. That's, that's how they would like to be established in there. They're very durable because you can just look in the eye and you can see the cells. There's a great thing about the eye is it's so accessible. There may be some settings where undifferentiated cells may have a benefit.


Brian Culley (Guest)
I don't know about that. We don't do that, kind of work. It hasn't to date been particularly successful. And there've been a number of failures. What we do is different. We are really doing transplant medicine. We fully differentiate these cells. They cannot then, convert into other types of cells or acquire, learned behaviors. Once they are introduced into the body, we develop functionally active retina cells. We place them in the eye and let them do their thing. They do, they integrate and they're stable and they're not rejected. We think that is really integral, that placement of the cells and that stable and graph mint and integration with the host is required in order to get the best possible clinical outcome.


Neil Littman (Host)
Brian, I want to sort dig into where you are in terms of clinical development. You had mentioned some of the safety that has been demonstrated over the last five years, or you talked about the efficacy, just to clarify for our listeners, if I'm not mistaken off Regene is currently in a phase one slash two eight open label dose escalation study, is that study still ongoing. What is the pathway forward for gaining approval? Have you investigated the R mat pathway for accelerated approval or talk about some future potential about actually being able to get to FDA approval and deliver these in a larger quantity to patients?


Brian Culley (Guest)
Yeah, we have our mat designation, probably the regulatory pathway is going to flow through some measurement of either growth of atrophy. I E the, how big is that wound in the back of the eye and or visual acuity? How many letters can you read on an eye chart? Visual acuity has been a really difficult path. Obviously there is no regulatory precedent. There's nothing approved. Most people shy away from visual acuity because it can be subjective to collect. It's really hard to deliver that it's hard to improve someone's vision. Most of the companies that are out there today are really focused on the atrophy. How big does that area of atrophy? That is how many cells are being are dying off. What's really kind of amazing about our study, which has meant we've been, we've treated 24 patients now with dry AMD, we're in the follow-up period.


Brian Culley (Guest)
Enrollment is complete, and we're just following the data to see what happened, but it does slow growing progressive condition. We have this one patient in particular, who actually ended up with a smaller area of atrophy after nine months. It remains smaller out to what we've reported the far two years. The reason why that's special is that human beings act the ability to regrow retina cells. You, you can cut your arm and your skin will heal, but if you cut your retina, it will not heal on its own. We have this problem where we have this atrophy that's growing, it's directionally only getting worse. We had a patient that received ourselves and their area of atrophy was smaller at nine months, stage smaller at 23 months. And meanwhile, their vision had improved. That's incredibly exciting to us because that is the magnitude of benefit to be able to stop that condition in its tracks, that would give us a lot of statistical power.


Brian Culley (Guest)
If we go after geographic atrophy or GA growth rate, you can imagine, this is what I often say is that, a lot of people are trying to show the difference between a car going a hundred miles an hour and a car going 80 miles an hour, right. Slowing the rate of something. We have a car now that actually runs in reverse. From a mathematical perspective, there's a lot of power to detect that kind of change when you can demonstrate that benefit in a patient that should not be able to do that. You will have none of those patients on the control arm. So it's really quite remarkable.


Neil Littman (Host)
And I really liked that car analogy. I think that's, that's helpful. Okay. I'd like to change gears and talk about one of your other programs, OPC one, which is a treatment that you're developing for spinal cord injury. OPC for our listeners is all Lego dendricite progenitor cells. That there's a little I guess, shared history, Brian, between you and where I used to work at the California Institute for regenerative medicine or CIRM. Could you talk about OPC one th and this is another cell that has, I think, a really interesting and unique history behind it.


Brian Culley (Guest)
Yeah. This is such an emotionally engaging program. What we're doing here is we're manufacturing a different cell type or more manufacturing oligodendrocyte progenitors, or just, colloquially we're manufacturing, new spinal cord cells. This is such a special program because it was in fact, the first clinical program that your organization CIRM, which has been so supportive of cell therapy, not just in California, what else, but it was the very first clinical program which serves supported. It's always been very important to serve. It's certainly important to me, the concept here is that when you suffer a spinal cord injury, which is typically from a car accident, or, mountain biking, shallow water hurting, diving and all of that, the wound or that injury in connection with the healing process cells die off, right? You have inflammation and cells die off. You end up with essentially a gap. Well, if you have a gap in an electrical wiring system, those electrons, those signals can not jump the gap.


Brian Culley (Guest)
The connection from your brain to your arms or your brain, to your legs, your brain, to your bladder, your brain, to your lungs, right, that connection can become dysfunctional or lost entirely. That's where you have become a quadriplegic. What we are doing is we are manufacturing the same cells that belong there in your spinal cord, the same cells that manufacture the installation for those neurons, for the axons, the wiring that's required for mobility, we manufacturer and transplant those cells to the patient about three to six weeks after injury. You don't have to be right there. It's not like stroke. You don't have to be there, right away when it happens, we let the inflammation go down. We put in our new cells and in doing so, what we're doing is providing the substrate so that people can regain the connectivity, especially in their upper extremities.


Brian Culley (Guest)
That's where we're focused in the clinic right now is getting people, upper extremity mobility so that they can feed themselves so that they can manipulate their wheelchair and have mobility so that they can use their phones and, have the normal fulsome relationships that we all want to have. It really has been such another great example of where small molecules haven't shown an ability to move the needle. We don't have anything approved for spinal cord injury, patients like this, but perhaps cell therapy will be the key that unlocks this problem.


Neil Littman (Host)
Brian, can you talk about where you are in terms of clinical development of OPC one?


Brian Culley (Guest)
Yeah. 25 patients have been treated with OPC one 95% of them have successfully Brafman, the eye. You can just do an MRI and you can actually see where you put those transplanted cells. Again, like the eye, the spinal cord has immunoprivileged. There's not a lot of white blood cells floating around that would cause rejection of the transplanted cells. So we've seen incredibly encouraging safety data. The, the cells and the transplant have been tolerated very well, multiple years, and then turning to efficacy. It's been very encouraging to see that one third, eight of the patients. One third of the patients that we treated gained, what's called two levels of motor activity. So motor activity is a standard tool. That's used to measure the status, the range of capabilities of somebody who has suffered a spinal cord injury, and a third of the patients gaining two levels is very significant.


Brian Culley (Guest)
It's the difference between someone who requires 24 hours of healthcare and someone who only needs a few hours a day to have, their laundry loaded into the machine, because their wheelchair doesn't fit into the pantry where the laundry mat is, right. That sort of thing. It really is a massive change in terms of quality of life and independence, as well as the burden on the healthcare system for enabling individuals to have the freedom, to get around and do things that they want to do simply by getting them some additional upper extremity mobility.


Neil Littman (Host)
It's really incredible. I would assume similar to dry Andy, there's really no available treatment options today for, for patients. So, yeah, it's really incredible the fact that these Hells, these cells have w one question that I wanted to dive into is, obviously lineage is developing. I guess what I would consider a, a platform technology can have a broad, host of applications. How did you decide on dry AMD and spinal cord injury as your lead indications,


Brian Culley (Guest)
But some therapy my bed. They were selected before I joined the company. However, in hindsight, they were good decisions. The reason why I say that is that in the early days of cell therapy, there was a lot of ambition. People thought, oh, we're going to solve Parkinson's and we're going to solve autism and all of this stuff. Maybe someday we will, but the industry really needed to start where the probability of success was the highest, because that would then attract further investment and interest in the field. Going after the eye, whereas I said before, you're able to see what's going on or the spinal cord, where you can do an MRI and it can track the status of these graphs. That's completely different than injecting cells systemically into a bloodstream. You don't really know where they go and what they're doing. Also going into the eye and the spinal cord, where you have much lower risk of rejection.


Brian Culley (Guest)
That's a, that's a really great advantage compared to the systemic approaches that are more ambitious. Certainly it doesn't hurt to have a huge commercial opportunity and, negligible competitive threats, because that, again helps attract the investment that allows you to go through and, create very attractive product candidates that are usable ultimately at the bedside. I think that what's really kind of exciting. I don't think appreciated about lineages, that the cell lines that we use have within them the capacity to become any of the 200 plus cell types in your body. Right now we're making retina cells and we're making spinal cord cells, and we make these dendritic cells for cancer, but there's 197 other cell types out there. There's a massive platform technology residing within this one company. I sometimes jokingly say that, it's being the Amazon of cell therapy. You start by just selling books.


Brian Culley (Guest)
Now you can buy anything you want and Amazon. Right now we're starting in the eye, we're starting in the spinal cord. We have opportunities where we could go into all sorts of different areas. I look forward to, when we get to that scale, being able to consider where we might go next. In fact, we just a couple of weeks ago, we dosed a patient with the TeleForm maculopathy, which is not the same as dry AMD, but it's another kind of condition that may perhaps lend itself to treatment by transplant of RPE cells.


Neil Littman (Host)
Brian, I may have to borrow some of your analogies. I, I, I liked that AWS analogy as well. We could probably talk about this for the next two or three days, but I do want to just maybe ask one final question. And, and that is, you had mentioned you have the ability to produce all kinds of different cell types, in the cell therapy world, as you've no doubt heard, said many times, the, the process is the product. Could you talk about the, the, the manufacturing process? That something that you do in house? Do you contract out any, or all of the manufacturing process?


Brian Culley (Guest)
Yeah. Manufacturing is the foundation of everything that we do the old saying of garbage in garbage out. There's many steps along the manufacturing process, and you have to have control of them all along the way, because remember, we're starting with these undifferentiated Puri, potent cells, and they're just waiting for a signal, right? Do you want me to become a kidney cell? Do you want me to become a liver cell? And so we say, no, no. We want you to become a retina cell. We expose them to different chemicals at different concentrations and different times, and in different ways, and in doing so, we are trying to mimic the natural developmental biology that these cells would be exposed to naturally. In doing so, we are manufacturing pure populations of RPA stem cells, and there are no residual undifferentiated pluripotent cells after we go through the process and we have all of these release criteria, we're able to monitor, not the clumsy way that we used to do it as an industry in the past, which was just karyotyping right.


Brian Culley (Guest)
Counting the chromosomes to make sure that things are still fine. Now we're doing whole genome screening and we're looking at functional activities. Of course, things like viability of the cells, a dozen plus surface markers to make sure we have the right cell types. We just, we have the tools now to do this as an industry. So, as it gets faster and easier, and the quality goes up, we'll gain more control over how we use them. In what way, which ultimately of course is going to lead to better clinical outcomes. So we do all of this. In-house, it's in my mind, it's too important and too delicate to you. Can't throw it over the wall. It's just, that's fine if you're doing a small molecule, but you don't throw cell therapy over the wall and ask a contract organization to do it for you. I think it's far too important to be right there, monitoring it every step of the way and in doing so I think that increases our probabilities of clinical success.


Neil Littman (Host)
Yeah. I think that's a really important point, right. That a lot of folks, maybe don't don't really think about, right. It's controlling the manufacturing process. Right. Making sure that you're investing in that process because at the end of the day, it's that process that is producing the, the product, right. They're one in the same in the cell therapy world. The tighter control you have over that part of the process, the higher, your probability of successfully developing the right cell, which gives you a higher clinical probability of success. Brian, with that, I think we better call it a wrap. I would like to thank you very much for joining us and for a really wide ranging and really great conversation.


Brian Culley (Guest)
And it's been a lot of fun. It's been my pleasure. Thank you guys.


Danny Levine (Producer)
Well now, what did you think?


Neil Littman (Host)
I thought that was a great discussion. I mean, I think we covered a tremendous amount of ground, I think Brian has a really unique perspective on the cell therapy field. In general, you heard him talk a lot about, at least towards the end, that process, and just how critical it is for a company, at least in Brian's perspective to control the entire manufacturing process. Listeners on this show have heard us talk a lot about this idea of that. The process is the product. So you can't really separate the two. So I thought that was particularly interesting. I was also really fascinated to hear about some of the MOA in terms of how opera region actually doesn't graph that it helps reconstitute the, the function of the cells that have been damaged. It doesn't just work by the Paragon effect and reduce recruiting indogenous cells or factors to help repair some of the existing cells.


Neil Littman (Host)
It's actually in grafting and, and Ren, reproducing functioning cells. So, I mean, in many ways, that's the holy grail of cell therapy. A lot of itself doesn't actually work that way, but I think that was really fascinating to dive into.


Danny Levine (Producer)
The company's lead indication is for dry AMD. It's always interesting when you've got a technology that could be applied so broadly, how a company, prioritizes indications do you think this is a, a safer place to start for an off the shelf cell therapy?


Neil Littman (Host)
It certainly seems that way. I mean, you've heard Brian talk about why the company chose to go into the eye and into spinal cord injury or, and into the spinal cord. They're both somewhat immune privileged sites. I think there are a lot of benefits to be had by going after diseases that affect these immune privileged sites, that there's less fear of an immune response to the cells that also leads to perhaps lower doses of immunosuppressive drugs. You heard Brian talk about how they were trending in that direction with opera region. So, yeah, I think it's certainly makes a lot of sense to go after these sites with off the shelf therapies,


Danny Levine (Producer)
The early successes within cell therapies have really been dominated by cancer and car T therapies. It was interesting to hear about the origin of the cells. Lineage is developing, does this in some way, harken back to the vision people had initially for regenerative medicine.


Neil Littman (Host)
I think in many ways it does. I mean, each of this, each of the cell lines, I think really have a pretty fascinating origin story behind them, which is why I asked Brian the questions. I think in many ways that the promise that most people think about in terms of regenerative medicine is, replacement cells, replacement, tissues, replacement organs, right? We're, we're not there yet, but what lineage is doing it is definitely know replacement cells and cells that are actually in grafting and reconstituting some of the lost function from the areas that have been damaged. Yeah, I mean, I think in many ways, this is the promise of regenerative medicine. Now it's still early, these programs are still in clinical development, there's a long way to go, but yeah, I think this is certainly exciting what lineage is doing. Their lead programs are very exciting and they hold a tremendous amount of promise.


Neil Littman (Host)
Not only that, I mean, there is clinical data demonstrating, safety end, early signs of efficacy.


Danny Levine (Producer)
As you think about what they're trying to accomplish, where do you see the biggest challenge?


Neil Littman (Host)
Yeah. I mean, I think there's obviously a host of challenges scaling up these technologies, right? Demonstrating efficacy in larger trials. There's a lot of anecdotal evidence for various types of cell therapies working in, any equals one type environments. Can these technologies demonstrate efficacy in much larger clinical trials? So, there's always a biology risk there. We talked quite a bit about you manufacturing, right? So there's certainly risk in manufacturing. Can you scale up or scale out the manufacturing process to produce enough cells to meet the demand for future clinical trials or the commercialization of these cell therapies? Of course, delivering the cell therapies has a host of other challenges that we didn't get into on this call, but, supply chain logistics, those are all challenges that are associated with, cell and gene therapies, because it's very different than infrastructure that, the, the biotech and pharma industry has in place today.


Danny Levine (Producer)
Although it was interesting to see lineage, make the decision to do it's on manufacturing, which seems to be driven in large part as an effort to mitigate risk. You think it makes sense that they're doing that?


Neil Littman (Host)
I mean, I, I certainly does. I mean, if you think about what Brian said, I mean, they are controlling the process in an effort to help increase the probability of their cells being, the right cells in terms of purity and by doing so that increases the likelihood of demonstrating efficacy in a clinical trial setting. By controlling that process, I think, their point of view, which I agree with is they are greatly able to reduce the risk of, clinical development, making sure that they are producing the right cells, because at the end of the day, that's critical, right? I mean, you have to produce the right cells consistently batch after batch. I think it's Brian rightly said, why would you throw that over the wall to someone doubts or if that critical aspect of, of your programs.


Danny Levine (Producer)
Well until next time.


Neil Littman (Host)
Excellent. Thank you, Danny.


Danny Levine (Producer)
Thanks for listening. The bio verge is a product of bio Virginia investment platform. Visionary entrepreneurs with the aim of transforming health provides access and enables everyone to invest in highly vetted healthcare startups on the cutting edge of innovation from family offices, registered investment advisors, and non-accredited individuals to learn more, go to bio verge.com. This podcast is produced by over by the use it for this podcast is provided. The Curtis is Jonah Levine collect.