Have you ever thought about having replacement parts for your body? It sounds like science fiction, but it’s now as real as the eyes you’re using to read this, thanks to cell-based therapy. Brian Culley is one of the leaders in this field. He is the CEO of Lineage Cell Therapeutics, a company developing treatments for multiple indications based on their proprietary cell-based therapy platform. Leveraging in-house manufacturing, they are attacking multiple indications from ophthalmology to immuno-oncology. In this episode, Brian joins Ammon Rivera to explain what their strategy is, where they are currently in the development process, and where they’re going from there.
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Can Lineage Cell Therapeutics Proprietary Cell-Based Therapy Platform Change Treatment Development?
Our guest is Brian Culley. He is the Chief Executive Officer or CEO of Lineage Cell Therapeutics. They’ve got some cool things going on. We’re going to get into the platform they’re working on, some of the indications that they’re going to be able to tackle with that, what their strategy is and where they’re going from here. Before that, we always like to get into the background a little bit of the individual that we’re talking to, the story of how it is that you ended up in the biotech industry and where you ended up where you’re at. With that being said, what were the driving factors that led you in this direction?
I’m into the field overall. As a little kid, I was interested in the life sciences like a lot of people. Biology was an interesting subject. Even going back earlier, I remember as a little kid almost doing experiments, filling up a cup of ice with water right to the very rim and asking myself whether the water would evaporate faster or the ice would melt faster and overflow the cup.
I like to think of that as my first ever experiment. I’ve always been curious about how the world works and that naturally is going to send someone up a path through university and beyond of continuing to stay in the field. The fact that continues to healthcare, medicine and improving the human condition is a big bonus.
You’re talking about that interest from an early age. I’ve interviewed other individuals that say a similar thing. Where I question a little bit is how is it that you went from that to healthcare? What was the pivotal experience that caused you to go the route of treatment development or drug development?
It’s not that exciting. It was probably my undergrad at Boston College. I went there to the School of Arts and Sciences because I was interested in the sciences. There were two tracks. You either went pre-med or into a research lab. There’s teaching and all sorts of other things. In terms of chunky responses, those were the two tracks. I wasn’t particularly interested in being a doctor. I went through the path of becoming a research scientist and then migrated back onto the business side later in my career.
What were some of the key pivotal experiences that you had earlier on in your career that you felt put you on the path to this position that you’re in?
I get questions like that from time to time. People are like, “How can I become a biotech CEO? What’s the right path?” There are many paths that you can get there. Mine was a little strange. I fortuitously, in my career, had several times where my supervisor left the company. I always saw that as an opportunity. Some people wait until someone new is hired. I always tried to take that person’s job because it was vacant. I was able to accelerate a career trajectory faster than some others. I also tried to be thoughtful about it and think about how I could bridge from basic science into business.
I had a couple of steps along the way, working in areas like technology licensing, which is an in-between area, going off and taking business classes because I wouldn’t have been exposed to that otherwise. Going and getting an MBA were all things that helped me make a transition. Before I became a CEO, I worked in business development. You’re bridging the business side and the technical side. It was a long journey but directionally, it was always moving to the point where I could do a business job while still being grounded in the life sciences because I care about them.
There is a small little book I read a long time ago called The Richest Man in Babylon. It’s a fictional story. I don’t know if you’ve heard of it. It’s about someone who becomes wealthy and there’s a discussion in there. They talk about what are some of the principles that this person has lived. One of the chapters in there is called The Goddess of Good Luck.
They talk about when an opportunity arises, if you’re in the right place at the right time because you’re making certain decisions that have led you there, it doesn’t necessarily mean it’s going to be the exact one that you wanted always. Whatever that opportunity is, you capitalize on that. A bit interesting is when somebody would leave, it was like, “There’s an opportunity. I’m here. Perhaps I can step into this role.” You make the moves that you need to try to get in that direction.
Way back in high school, there was a sign in the football coach’s office, “Luck is what happens when preparation meets opportunity.” I don’t know why I always remember that because I didn’t play football but it’s a nice guidepost for life.
I appreciate you indulging that a little bit and giving us a little bit more about your background. We’ve got some questions for you at the end here that we’ll also touch on some of your backgrounds and give us a look into the psyche of Brian Culley. Let’s jump to Lineage Cell Therapeutics. Lineage Cell Therapeutics’ programs are based on the company’s proprietary cell-based therapy platform, associated development and manufacturing capabilities. There are a couple of different things here that we’re going to unpack. To break it down, Lineage Cell Therapeutics essentially has its platform that you’re using to develop cell therapy treatments that can go after multiple indications.
The simplest way I might convey it is we can make replacement parts.
For some of the folks out there that watch some sci-fi or anime stuff, we’re on that track.
Except for it’s real. It’s not even sci-fi.
What’s the genesis of Lineage Cell Therapeutics? Tell me a little bit about that.
It’s an old company but I like to think of this era as starting around 2019, in connection with two transactions that the company did right after I joined in late ‘18. What we did was spun off a lot of early-stage programs that had long timelines. We also acquired a public company that had a couple of programs in the clinic. In connection with that transition, Lineage was essentially birthed. I renamed it Lineage. That’s how it started.
The reason for that is the three programs that we had at that time all had a common theme. That theme was that we could manufacture a specific cell and use that to replace a function that your body has lost. In 2019, when we changed the name of the company Lineage shortly after I joined and bought one company and sold another, that put us on a much narrower focus and goal of using these specific cells as a new medicine to treat various conditions.
You explained the term lineage when Lineage was birthed through this process but why the name Lineage Cell Therapeutics?
What we do is we start with a vial of frozen cells but these are not normal human cells. They’re special because they can be multiplied. You provide them with nutrients and they can divide which that part is common. What’s special about them is you can continue that process. You could double a penny every day for a month and have approximately $1 billion. It’s the same idea with these cells. You can feed them, they’ll divide and you can continue that process forever because they are essentially unprogrammed. They’re like blank slates. Every cell has not yet decided what they’re going to become. They’re not kidney cells, liver cells, brain cells or anything. They’re just blank.
What we do is we put them through a process. We can call that a recipe. Through that process or recipe that we use, we can manufacture specific cell types. We might make retina cells, a certain blood cell or the cells that comprise your spinal cord. That process of converting a cell from a blank cell called a stem cell into a specific and discrete cell type follows what’s called a developmental lineage. The cell is exposed to various conditions. In doing so, it turns into a bone cell, a brain cell and a blood cell. That’s the inspiration for the name. We can control those lineages to manufacture only the cell type that we want at the end and that’s the product.
Where do you get the original set of blank cells that you’re going to then develop?
These are three potent cell lines. They’re called ES cell lines from anonymously donated medical tissue that were established many years ago. There are about 400 of these cell lines that are eligible for federal funding and we happen to use one of those cell lines. The magical feature or attribute of these cells is that they can divide without changing, so you can use the same cell line forever.
We’ve been using this cell line for many years. We never have to go start over. You can, for example, take these cells, grow them up to a great number and freeze them down. You can come back many years later, pull a vial out of a freezer, grow a bunch more and put those in the freezer. You have an infinite supply of these cells, which is powerful and helpful in this setting.The common theme of all programs at Lineage Cell Therapeutics is to manufacture a specific kind of cell and use that to replace a function that your body has lost. Click To Tweet
You can essentially program these cells and that’s how you’re able to go after the different therapeutic areas. I spoke with another company that I had on the show. The CEO’s name was Kleanthis Xanthopoulos. They were developing immunotherapy for cancer. We talked a little about pluripotent stem cells. They’re down in San Diego as well, Shoreline Biosciences. We talked a little bit about these pluripotent stem cells and I thought it was a little bit interesting. I’m digging the conversation in this so far. What are the challenges that we have in developing a treatment like this?
The biggest challenge is manufacturing. The reason for that is unlike using a small molecule or maybe an antibody, small molecules, what we usually think of as drugs and pills in bottles, is a discreet and singular molecular structure. If you need to make a molecule because it’s been shown to be effective as a medicine, you’re following some Laws of Chemistry, maybe physics to make it.
You’ve got your starting material and run it through a few reactions. You have some loss but there are rules which govern how to make that material. Chemistry is chemistry, so you will get the material you want to make. Cells are millions of times more complicated. Each cell is comprised of many billions of molecules themselves.
Manufacturing cells as a product is far more difficult than manufacturing a single molecule. One of the great things that have happened in our industry and specifically at Lineage is we’ve developed tools by which we have much greater control over this. Maybe you and Kleanthis Xanthopoulos might have talked about this. It’s hard.
It’s critically important. It’s foundational in our industry that if you’re going to have something approved by the FDA, the FDA is going to insist that it’s the same thing every time. You can’t test one therapy and then treat people commercially with something a little bit different each time. You have to get the same thing. That’s difficult with cells but the industry has moved and advanced. We have new tools and techniques by which we can do that. It is starting to open the whole field of cell therapy in a way that was a little bit out of reach years ago.
That reminds me of something I came across years ago, phage therapies or treatment for superbugs. There’s a challenge with these bacterial infections building resistance to the antibiotics that we have. I watched this little video where they talked about it. The big challenge in getting this approved is you can go get an emergency approval in the hospital with an individual but it’s case by case. They cannot produce a mass treatment in this because you can’t produce the same treatment every single time, which is the challenge there.
If pizza could cure cancer but it’s only Chicago pizza, if you go to San Francisco, it’s still pizza but it’s different. That’s a challenge. It’s called reproducibility. You have to make the same stuff every time.
I’m curious as to how people’s bodies respond to this. From the trials that you have and in the research that you have done, have we gotten to the point where we can see how individuals’ bodies adapt to this?
It’s encouraging. Generally speaking, cell therapy, using whole cells, has been very well-tolerated as an approach. Unlike if you think about the setting of cancer where you could be putting toxic poison into people to kill cancer but it also kills the healthy cells at the same time, that’s collateral damage and causes a lot of side effects. Generally speaking, cell therapy has been incredibly well-tolerated as an approach.
I’m covering a lot of different territories when I say cell therapy. There are many different ways that it can be utilized. One of the things that we’ve seen in our hands is that we’ve treated across our 3 programs, probably more than 60 patients. We’ve never seen a single case of rejection. If the cells are going to be integrated and become part of your body forever, they need to be well-tolerated. You can’t reject them.
Highlighting how cell therapy has matured as an industry, if you go back, people used to worry and say, “You can’t be transplanting liver cells into this person. They’re going to reject them.” We’re finding ways, things like gene editing and other approaches. There are ways of being able to help stably and durably integrate the cells into patients. It’s another great example of how this field is set up for explosive growth by solving some of the key problems.
Let’s jump to a discussion on the Lineage platform itself. You’ve touched on some of these things throughout our conversation thus far because, naturally, some of the questions I’ve asked have led to that. On your website, the Lineage platform, there are three stages here. You’ve got expansion, differentiation and development.
In the expansion phase, you can click on each of those and they’re interactive. They give you a little bit of information on each of those stages. We talked about the expansion stage. That’s the stage where you’re taking these cells that you already have. You can grow them, freeze them and then be able to have those available to you infinitely. On the differentiation page, let’s talk a little bit about that.
This is the recipe. If the expansion is flour, you’re starting with the flour. Differentiation is deciding whether you’re going to make bread or a cookie. That’s the recipe. The recipe involves a whole bunch of different conditions, the things that you do to the cells, how you treat them, what you expose them to and different chemicals that you would expose them to. What we do is we try to imitate the natural and normal developmental process.
For example, the human body has a way of figuring out how to make a retina cell from one of these pluripotent stem cells. We, as an industry, have figured out that recipe. There’s a gentleman who’s published exactly that paper. “Here’s how you make a retina cell.” We use a lot of his principles. A lot of our intellectual property is coming up with these very special recipes to make the specific cell type. The second step is differentiation, turning the flour into bread and only bread, no cookies. That’s how we do it.
What we’re trying to do is come up with essentially pure populations, which we’ve been very successful at doing. When we make retina cells, there’s a Dove soap. They’re 99.5% pure retina cells. We cannot detect any of those original pluripotent cells. They’ve all been converted into more mature, specific cell types that we test for function, activity and identity. That’s differentiation. With that step, you have a nice vial or container of pure retina cells.
Maybe this next question is going to be quite a bit technical, at least for me or I don’t know if you can maybe even answer us on this episode. No alterations are made to the cell’s DNA. From my side of the table, not having a strong science background and trying to understand this, you’re talking about this recipe to make bread only versus cookies. How does that not interfere with the cell’s DNA?
It’s because we are imitating the natural process, so the cells are only going forward. At the time of conception, just one cell has within it the capability of making the entire body, all 200 cell types. Those are lots of different recipes that your body has to follow. Your body never uses crisper or gene-editing tools. We are aware, as an industry, that gene-editing can cause some safety signals.
We have had, in some cases, severe instances where messing around with the genome causes some serious health concerns. We don’t do that. We don’t manipulate the genome. We imitate what naturally happens in your body to manufacture its developmental biology, which fortunately for me, also happens to be my background. That has been something we’ve done.
There are other techniques I could mention. Your audience probably has heard it. You can take cells from a person, such as from their skin and treat those cells in a way to almost erase their memory so that they can start to have some of these same capabilities. Those are called IPSC cells or IPS cells. That’s the same thing. It’s a very harsh exposure to the cells.
The cells never forget that they used to be skin cells, even when you force them to behave more like our pluripotent stem cells. What this means is that we’ll ultimately be shown to have a safer approach because we’re not forcing the cell to behave unnaturally. We’re not torturing it in any way. We’re following the natural inclination of it to become different cell types in your body.
One of the other strengths that Lineage Cell Therapeutics has going on is its in-house development and the interactive side of the website. Cell Cure Neurosciences is a subsidiary of Lineage Cell Therapeutics. If I understand this correctly, it’s located in Israel. Is that correct?
We have over 40 employees at a manufacturing facility. You’re showing four of them. These are the folks who have developed the skills and created a lot of intellectual property. They manufacture our clinical material. It’s important when you’re manufacturing a complicated biological cell. It’s very difficult to ship that out to a contract organization and say, “Send me back retina cells.”
It’s important to be able to control your manufacturing and generate your patents. The most advanced program that we had, which we partnered with Roche and Genentech in a $670 million deal, was invented in Israel. We started to build capabilities and add staff and team members there. That’s where all of our programs are being manufactured.There's something really powerful about just asking a simple question. If you don't, you're never going to know. Click To Tweet
I love how you have your website because you can interact with it. You can go to different places. We talked about expansion, which is that early step and differentiation or the recipe. Here’s the development side of things, which we can go after these different indications. It tells us a little bit about the development stage. We can go to your pipeline and see what you have. Let’s talk a little bit about this and where you’re headed in your strategy moving forward from where you’re at.
The output from the differentiation might be thousands of vials of pure retina cells. That would be clinical-grade material that we can use in clinical trials. When we manufacture retina cells, we’re using those to address dry AMD, one of the leading causes of blindness. When we manufacture oligodendrocytes, we’re using those to treat spinal cord injuries so helping people recover mobility after they’ve been paralyzed by some spinal cord injury.
We might manufacture dendritic cells, which are part of your immune system and we can put antigens in those dendritic cells. We use those to destroy tumors. These are the three clinical-stage programs. We also announced a new program, which has not gotten into the clinic yet but we’re going to be making auditory neurons to help with hearing loss. That’s an exciting new initiative that we were able to create in-house. That material that we manufacture in step 2 becomes the medicine that we’re using in step 3, which is developing new therapies for these unmet needs.
I’m in Utah and here in Park City, there is a clinic there. I read about this billionaire who started Bulletproof Coffee. It’s putting butter in the coffee because your body needs fat. I remember reading this article where he was saying, “I’m going to live until I’m 120 years old.” He goes and gets these stem cell injections into his joints to try and keep his joints healthy, young and all of that.
It’s much different than getting a joint injection to treat, whether it’s retinal damage or cancer itself being a challenging thing. What you have announced is what you have announced. You can’t necessarily get into specifics. With the types of indications that you plan to go after, do you see this being able to be applied? We could go after whatever indication we want to go after with this. Do you have a specific strategy in mind where we’re going after these, this is the reason why and we’re going to stay that way?
Both. There are places where it makes more sense. First, I want to make a distinction that the billionaire getting the injections of stem cells. If you’re a billionaire, you can afford that stuff but that’s usually a very unregulated process. If you don’t have controlled clinical testing, I have no idea if that stuff works. That’s not what we do. You and your readers know that.
We exist in the highly-regulated environment of the Food and Drug Administration. We’re trying to demonstrate irrefutably that our therapies have an effect. We do not charge people to participate in our clinical trials. With that as a backstop, that individual and maybe many of us living to 120 might be very attractive but not necessarily as attractive if you lose your vision, hearing and mobility.
What we’re trying to do is help improve people’s quality of life, what sometimes is called health span, through our regenerative medicine approach. There are about 200 cell types in the human body. There are subtypes and everything but our cells are capable of becoming any of all those 200 cell types. You need to work on it and do the recipe.
We are a business and a public company trying to create medicines and become a profitable business in that regard. We choose areas where we think we can have an advantage and demonstrate what’s possible. I sometimes say that, at one time, Amazon only sold books but now you can get everything from Amazon. That’s inspirational for us.
We have these three clinical programs that I’ve described but longer term, we’d like to be able to go into new areas. Like what I said with hearing loss, that’s a brand new area. We did not have to acquire that technology. We built that in-house and we can do more. People have already started thinking about things like cardiomyocytes for heart disease or islet cells for type 1 diabetes. These are massive opportunities. We’re focused and committed to the areas in which we’re operating. Longer-term, with the right resources, opportunities and partners, we could go into a lot of other areas as well.
You gave a great explanation there of what your strategy is moving forward. Is there anything else you want to add to share with the readers out there about Lineage Cell Therapeutics?
This is exciting. Some of these individuals that are on our website I’ve spoken to myself. They’ve had life-changing experiences going from being unable to shrug their shoulders to being able to type 35 words a minute. Going from having a poor vision to having an improvement in vision. For your area of atrophy, the wound in your eye gets smaller. That doesn’t happen naturally. Human beings cannot regrow retina tissue. It has to come from outside the body. The most exciting thing is the impact that we’re able to have on patients above and beyond what the typical approaches of small molecules have been able to do in these areas so far.
One question before we do shift to the final three that I forgot to ask was how you see the application of this in the marketplace. Would you mind touching on that with us briefly in terms of how you see it being applied?
We’re trying to simplify it. I’m glad you asked that because it’s the third example of how the field has matured. It used to be the case that if you want to administer these cells to a patient, you might need to ship the cells to the patient the day before, where they get washed, handled, counted and replated. There’s a lot of complexity associated with it. We’re getting rid of that complexity. We have developed a formulation or a preparation of ourselves that is in a frozen state. You thaw them for about five minutes and they go right into the needle and the patient.
As a business, we also are trying to simplify some of the complexity of cell therapy. In the case of the spinal cord program, we’re also working on a new device instead of having this enormous scaffold that sits over the patient. We’re starting to test in the clinic this teeny-tiny device that sits on their back. I won’t go into all the advantages of why that’s important but that is an important maturation of the field to make it easier to use for the surgeon or the physician and easier for the patient to obtain and have these be global therapies for these individuals.
Let’s jump to the final three here. The first question takes us back to the discussion we were having in the beginning. If you could go back in time and give yourself advice, what would that advice be?
Ask more questions. I’m fortunate that I’ve learned a lot. I had some wonderful educators and mentors in my life but there’s something powerful about asking a simple question. If you don’t, you’re never going to know. You might have to go and look it up after. There are many opportunities in my life where if I ask a few questions, it’s a great opportunity to learn something from someone and retain that forever. That would be my advice.
That’s good advice. I should keep that in mind. A lot of times, people are afraid to ask more questions. There are all kinds of reasons why they may feel that way. One of those is you don’t want to look stupid. You’ll never know unless you ask. It’s not stupid to ask unless it’s pretty basic. I have a list of books on Audible and a stack of books at home that I haven’t fully gotten to yet. Some of them I’m halfway through. What book or books have you read throughout your career or life that you feel has had a great impact?
This won’t be on your list. There was a book in college that was the textbook for a recombinant DNA course. It was filled front to back with deep genetics and recombinant DNA principles back from polymerase chain reaction to gene editing. Back then, I wanted to be a gene jockey, change genes, see what happens when you change them, figure it out and do site-directed mutagenesis. I love that book. It helped me appreciate and understand science. It was one of those cases where it wasn’t just learning material like, “This is a nucleophilic substitution reaction. Memorize it.” It was more exploratory. It was a great book.
What’s the name of that book?
It was probably something like Recombinant DNA Technology Volume 1. This was before Kary Mullis won the Nobel prize for polymerase chain reaction. This goes back to the early ‘90s. It was a great technical manual and out of date. No one’s going to go read it now but if it’s still around and some version has been updated, it’s probably short because it’s a lot easier to edit genes now. The tools were crude back then but it was a fun book.
The last question is, where do you think the industry is headed, biotech and pharma, in particular?
Up into the right, the breakthroughs are incredible. I had a very dear friend who shared with me that his wife had a cancer diagnosis, a particular cancer that I happen to know fairly well. It is amazing because one of my family was diagnosed with that same cancer years ago. At that time, there were no approved therapies. Now there are six.
The pace of innovation has been so exciting. The problems are getting harder because we’ve been able to solve some of the easier ones. With motivation and incentive, everybody wants to avoid pain, discomfort and suffering. Healthcare is going to keep kicking butts and taking names. It’s going to be a great couple of decades ahead.The pace of biotech innovation has been so exciting. Now the problems are getting harder because we've been able to solve some of the easier ones. Click To Tweet
From a financing perspective, with everything happening the way it’s happening, there’s a lot of speculation and discussion on what’s going to happen to the economy with inflation and interest rates rising. Real estate will resonate across the board. What that’s going to do to affect the economy? Economics expands and contracts. I was talking to some people that said they’ve been through times where in the biotech world, there was a bit of a contraction in terms of people willing to invest.
From what I’m seeing, based on what you were explaining, this desire for us to develop better treatments to attack harder problems that we have is going up but nothing goes up forever. How do you see it from a monetary standpoint with everything that’s been happening the last couple of years? Do you see there being a plentiful investment or not?
The investment will always be available for quality. As long as you’re providing a solution in a capitalistic environment that we have, you’re going to be able to find capital if you offer a compelling value proposition and a great story. You can get the skills to convey that in a way that people can understand. Sometimes too much money does come into an industry. There is filtering. The cream will rise to the top. People were originally built to last 40 or 50 years. We’re going way past that, which means we’re always going to have degeneration. Our bodies are being asked to go longer.
We’re always going to have illness and sickness. There are going to be people who want to work on that. Nobody wants to die young. We’re always going to have a nice core of opportunity. People sometimes think, “Pharmaceutical companies, bad guys.” It’s untrue. Everyone that I know is deeply committed to trying to develop new medicines and make the world a better place. Even if you take away some of the financial incentives which exist and the market protections, you are always going to have a steadfast core of people who simply want to do well by developing therapies for humankind. It’s a great play. I’d rather be doing this than selling breakfast cereals.
From a health perspective, eating breakfast cereal is probably not the best choice.
It depends on the cereal. There’s someone who’s going to be inspired by making better breakfast cereals out there. It’s happening. Go down the grocery aisle. There’s innovation in the breakfast aisle and also abundant innovation in the healthcare world. Lineage has been very successful in raising capital. We got a $50 million upfront payment from big pharma to partner with one of our programs. If you can show the data and the evidence that you have something compelling, you’re going to be able to find the funding for that.
I don’t know how up-to-date because this is Crunchbase but it shows a little bit of a highlighted backstory here. That $50 million you just talked about, you wouldn’t include that in the funding side of things or did that happen after?
This was announced at the end of December 2021. I don’t know whether it’s reflected in Crunchbase or not. We have done our annual reporting. It should be in there but it was a traditional license agreement, a smaller company with big pharma to help them access their capabilities and increase the probability of success of that program. We came with a $50 million upfront payment that we’re using in part to reinvest in other programs and expand the company. That’s going to help us be successful.
I appreciate it. Thanks for coming on. It’s great to chat.
Thanks so much. Take care.