All right, we'll go ahead and get started. Good afternoon, everyone, and welcome to the second day of the Citizens Life Sciences Conference for the first time here in Miami. It's my pleasure to introduce Sana Biotechnology. Presenting for the company or chatting with us about the company is CEO Steve Harr.
Steve, welcome, and thank you for this. I never know exactly who's in the audience or who's listening, you know, on the webcast, whether they know the Sana story or not. I would love to start off maybe in two to four minutes with an overview of Sana before we dive into some specific questions.
Sure. First of all, thank you for having me and the company come down here and enjoy beautiful, sunny Miami. Thank you people here in the audience and to those listening online. You probably know before I get started, we will make forward-looking statements and check out our risk factors in our recently filed 10-K. They're. We try to do a very thorough job and help you understand many of the things that could go wrong. I don't think we'll ever capture all of them. We do our best.
Anyway, so Sana is about seven years old and started with the idea that you know one of the most important transformations over the next couple decades will be the ability to modulate genes and use cells as medicines. It's obviously been a pretty tough time in that space over the last few years.
While that's been you know a difficult macro environment, we've been making a lot of progress in really seeing that vision through. When we started, we really wanted to go after two separate and what we thought were you know kind of really large challenges in making that vision a reality. First off, like, almost every disease is caused by a missing cell or a damaged cell.
We've known for a while that if you can transplant organs or even cells, that that can have a profound therapeutic benefit for people. But it's been really limited in particular in the cell therapy side and the transplant side by rejection of allogeneic cells. If you put my cells or anybody else's cells into you, your body will see them as foreign, like a virus, and reject them.
The way people got around that was they've used your own cells or autologous cells. That's pretty limited in what you can do, and it's very costly and difficult to manufacture. People have been given profound immunosuppression, and that's led to side effects like cancer, kidney failure, bad infections and things.
We wanted to figure out, could we hide cells from the immune system? That's problem number one. I'm gonna come back to that in a second. Problem number two was you can more or less do whatever you want to a genome in a Petri dish, right? The scientists have made tremendous advances over the last couple of decades in how they can modulate and manipulate DNA and RNA.
But the difficult part is actually delivering those reagents into cells in the body. We wanted to go after in vivo delivery, and we thought if you can deliver the reagents in a cell-specific way that is specific, repeatable, and scalable, we'd be able to do something that was pretty magical.
That's basically what we went after and we've been making progress on both. On hiding cells from the immune system, the most important project that we're after there is Type 1 diabetes. Type 1 diabetes is a disease where the etiology is pretty clear. The immune system gets confused. It attacks a patient's pancreatic beta cells.
The beta cell is the only cell in our body that makes insulin. Until 100 years ago, it was a death sentence, pretty much instant, within a few months. People have done pretty well on insulin over the last 100 years, but even with the best possible therapy today, patients will live on average about 10 years less than they would if they didn't have the disease.
During that time, they're at risk of really low blood sugars and death, coma. They can get blindness. They can have amputations, kidney failure, heart disease, a number of different ailments. Their day-to-day living is really driven by this need to control their blood sugar and their insulin. It's a disease where we need to do better is basically the key.
There are about 10 million people that have this disease globally, around two million in the United States. It's also very prevalent and big issue. Over the last several decades, some progress has been made. I told you it's missing beta cells, right? I'm gonna use a different word. I'll call it pancreatic islet.
Think of an islet as a beta cell plus its support structure around it. A group in Canada figured out you could transplant pancreatic islets from a cadaver, and that patients would do profoundly well. They are off insulin for decades, potentially. That's not a scalable source. It's a very variable source. Every patient has to be on lifelong immunosuppression.
These aren't that many people for whom immunosuppression is better than insulin. Over the last five years, several groups have shown you can take stem cells and make them into pancreatic islets and transplant those. Now you have a more replicable source, it's almost certainly more scalable, right? You still have the problem of immunosuppression.
What we've now shown is through a series of first animal experiments, and now we've done this in a person. The person was in the New England Journal of Medicine last year. That's we've shown that we can make gene modifications to islets and transplant them, and the cells survive and function, and we're now out over a year doing quite well.
There'll be an update, I guess, Friday on those data at a diabetes conference. I think all of the component parts are there for a cure, right? We've been working on what we call a more scalable manufactured version. It's a gene-modified stem cell-derived islet. Hopefully, we'll have an IND and start our phase one study this year.
We can get into it pretty quick to understand if it's working or not. Once we know it's working, I kinda think of that this program as having, you know, once it works, then make sure we can scale it. I mean, that's step two. I think we have a very high probability, given what's happened, of this working.
Not to say biology doesn't humble us or humiliate us from time to time, but we've really, I think, seen a lot of progress in the field. That's part one. The other part we have is this in vivo delivery, and I'll make this brief. You probably know there have been a number of programs, or you may know, making in vivo CAR T cells.
That's what we do. It is, if in preclinical settings and in particular non-human primates, I would argue that we have a best-in-class drug both on safety, tolerability and efficacy. We have to see how that translates into people. T hat we're not sure it's best in class in people yet.
We hopefully will be starting that study this year and generating data as we move through this year. I think within a year we'll have an ability to give you real visibility into both of these drugs. That's a platform. We can do more than one thing. The first in vivo CAR T cell will be going into patients with non-Hodgkin lymphoma.
If that works and looks good, we will expand into autoimmune diseases, other cancers, and then we can go into a different target as well to go after things like multiple myeloma. That's kind of the company in a nutshell. I'm sure we have more in-depth questions. Turn it back to you, Reni.
Yeah. Thank you. Thank you for that overview, and very comprehensive. Let's dive in a little.
Hope I didn't put you to sleep.
No, no. That was actually really good. I was like, "I'm running out of questions now." Let's dive into the hypoimmune, right, platform, just maybe to let some of the investors understand, what are the actual gene edits that, you know, have taken place here? I t's been validated, if you will, with that one patient, and we'll talk more about that one patient, but clearly it's been validated even before that. Just what are the changes here which are unique?
Yeah. There are effectively two really important parts of the immune system. There's the adaptive immune system, which is T cells and B cells. B cells make antibodies. That's the part you hear a lot about. That's where vaccines go after, and that's relatively straightforward to deal with. You knock out two different genes to knock out things called MHC Class I and Class II.
All of our cells flash fingerprints of what's going on inside the cell all the time, and that's so that the immune system can kind of surveil our bodies, and we just that goes away. Now the immune system can't see what's going on inside that cell.
Other parts of the immune system, and particularly the innate immune system, have figured out, hey, if you've gotten rid of that fingerprint, I need to kill that cell. We need to figure out, in the context of knocking out Class I and Class II, how do you turn off the innate immune system? This is really, like, the key insight of the company. ,
Overexpressing CD47 in the context of knocking out Class I and Class II appears to really cloak these cells and hide them from immune recognition. They live and they thrive quite naturally. To be clear, there's only one cell that's ever been transplanted at scale frequently in humanity without immunosuppression. That's red blood cells. You think about it, we get the red blood cell transfusions all the time.
What's unique in our body about red blood cells is they don't express MHC Class I, they don't express MHC Class II, and they markedly overexpress CD47. Right? What at least that gives us confidence in is that there isn't some part of the immune system that's geared to kill cells like that, right?
We then went and we validated this, you know, in vitro assays, and then we did animal assays, first mice, then humanized mice, then we did this in non-human primates, across many, many different cell types and many different monkeys. We then moved into humans, and we've done this in two settings. One is we made an allogeneic CAR T cell.
With that allogeneic CAR T cell, what we showed is that there is no immune response to these cells and that these cells can survive and function. All of that was published. The immunology was published last summer in the Cell journal.
Then we've shown this in the Type 1 diabetes setting, which is more complicated because not only do you have to hide the cell from allogeneic rejection, again, meaning someone else's cells into you, but these patients have an autoimmune response. They already have a preexisting immune response to kill that particular cell type. We're able to overcome both the allogeneic and the autoimmune. I think it's pretty well validated now that this is a functional system.
We can get into that patient and the data in a minute if you like, but we've kind of looked across a number of different settings. Again, it doesn't mean that it will work every time. It doesn't mean that biology can't come up with something that really surprises us. The I's have been dotted, the T's are crossed in getting to this next step of development we hope is a functional cure for Type 1 diabetes.
So far it has worked in every system.
So far, it has worked.
It's been really good.
Yeah
which I think continues to expand.
Yeah
the platform. Let's talk about Type 1 diabetes. You mentioned the number of patients, and so this is obviously a multi-billion dollar opportunity. You mentioned the Edmonton protocol, where people have used cadaveric islet cells. You guys actually took cadaveric islet cells and then imposed this hypoimmune platform, or the gene edits, into that and inserted it into a patient. That's the data that we have on in the-
In the RV forum. Yeah.
You had always said, like, look, if it isn't rejected, I think within a month or two-
I said within a couple weeks. You could say, but to be safe, let's go to a month.
Yeah. You said, "If it's not rejected in a month, it's not gonna get rejected." That's in fact what we're seeing, right? We saw the 1-year data. I don't think we've seen the data. You guys have put out a press release talking about how all these metrics continue to be measured. Can you just take us through specifically C-peptide and just everything, the cells even, right? 'Cause I think you're doing MRIs. Just everything.
Yeah
that gives you confidence that, hey, this is doing well.
Yeah
is here to stay.
To take a step back and, Ren, thank you for kind of outlining it well, which is our goal is to do a gene-modified stem cell-derived islet. That's a very complicated manufacturing process. It takes us more time. As a way to understand the biology and the immunology, we gene-modified cadaveric islets, meaning a recently deceased person donated their pancreas, and the islets were isolated, and they were gene-modified.
We knocked these two genes out and made MHC Class I and Class II. T hat kind of gene is called beta-2 microglobulin and CIITA. And then we knocked in a gene that would overexpress CD47, and the cells were transplanted into the brachioradialis or forearm of a person with Type 1 diabetes.
This person had Type 1 diabetes since 1987 and hasn't made his own insulin since then. The way to measure what's happening is we kind of laid out three things. It's a relatively low dose, right? The first thing that you're looking for is a protein called C-peptide.
When islets make insulin, they actually make proinsulin, and as it's secreted out of the body, it's cut by an enzyme into C-peptide and insulin. It's a 1-to-1 ratio of C-peptide to insulin, and this person had undetectable C-peptide by laboratories for many, many years, right? First thing we wanna do is can we detect C-peptide? That means these cells are living and they're producing and they're functioning, they're producing insulin, right?
The second thing we wanted to see was would they function normally? If you give someone something called a mixed meal tolerance test, so just think of it as high sugar, high fat, meal, does the insulin go up, or do the C-peptide go up? Again, the third thing we were looking at is can you see them, visually? The best way to see this is a PET-MRI.
The PET scan has a tracer which goes to pancreatic beta cells. You know, as you might imagine, we don't have pancreatic beta cells in our forearm, right? If you're seeing, beta cells light up in the, arm, it's very indicative that the cells that we transplanted are still there and living. The fourth thing is we did some immune assays, right?
Those immune assays we're looking to see. What we did is we took the blood from the patient and tested against residual product that we had to see, hey, is there an immune response against the product? This program has met every single endpoint that we have. It's been, you know, first of all, safety, it's very well tolerated.
There have been no, you know, drug-related or drug, you know, potential side effects. The cells continue to survive. They continue to evade the immune system by these assays. They continue to be visible by PET-MRI out a year, and the patient continues to produce C-peptide and to see an increase when they eat. That's all we could really ask for out of the study.
There are some details in the data itself which we can get into, but, functionally, it's accomplished everything we hoped it would. To your point, you know, it's not surprising. No part of the immune system is emerging.
It's not like you have things that just sit around your body, and after a year or two, your body decides, that's bad, we should probably get rid of it, right? It's very quick at recognizing, you know, pathogens, whether that's bacteria. In fact, you know, it's all set up to deal with viruses, bacteria. Our immune system wasn't contemplating us transplanting cells.
There you go. This was that one patient.
Mm-hmm.
You already talked about why, you know, we had gotten these questions early on, like, "Oh, why don't they just work with the Edmonton protocol and just use cadaveric cells?" You mentioned, like, it's not scalable. There was a lot involved in trying to match, you know, the donor cells with the right patient, right? The health of the cells, everything.
Well, the only thing we match on is blood type.
Mm-hmm.
There's an Achilles heel in every system, right? Our Achilles heel is a preexisting neutralizing immune response against the cell surface protein will get us. You know, we have to deal with blood type, right? With the stem cell, that's easy to deal with. We have an O-negative donor. It's not easy. It's like that's a 0.5% of the population, so we had to find a young female O-negative donor, which I can get into why all those things are true. In this case, the donor had to match blood type with the recipient.
Right.
that was the only matching that had to be done.
Okay. Well, let's switch gears just in the time we have remaining, 'cause I know everyone's focused on SC451. This is your induced pluripotent stem cell product. You wanna file an IND and get into the clinic. Can you talk to us about, you know, the discussions with the FDA, the cGMP master cell bank, you know, that you, I believe you have now and you have the genomic stability. Just what exactly it's going to take to get that IND filed and move into the clinic?
Yeah. As I mentioned earlier, manufacturing these drugs is relatively complex but doable. The first thing you have to make is This, this all starts with one single cell, and that forever your product derives from that one single cell. From that one single cell, you'll derive something called the master cell bank, and that master cell bank is many vials of, you know, of cells.
That's frozen, and we will make drug product from that, hopefully in perpetuity, right? The testing around that super important alignment with global regulators, and that relates to a host of different things that we test on. Number one, just normal things that you'd hope we do, like sterility, right? That's super important. That's kind of the parts of GMP or good manufacturing practice.
The second is every time our cells divide, it kinda makes a mistake or two. In our 30 trillion cells in our body, we probably have every single mutation you can think of. We have a system that's set up to control that, right? It's very, very rare. It takes many years typically for a cancer to form, if ever.
We're doing something different. We're growing these cells up. We're putting them in a growth media that selects for cells that grow quickly, essentially, right? What we had to make sure of is we weren't selecting for tumor cells, right? That was really hard. We were selecting for tumor cells for a long time.
We were seeing certain cancer-causing mutations pop up. The real kind of most important thing the company did over the last few years besides this immunology experiment was figure out how to make a master cell bank, like, gene-edit cells, so you have to break DNA, cut it, paste it back together again, in ways that allowed for genomic stability over many, many, many, many divisions.
Because, like, if you think of average dose is around 1 billion, that means, you know, just call it 1.5 billion if you have testing, that means you need 1.5 trillion cells to treat 1,000 people, right? The math gets so big very quickly, right? This is a disease with 10 million people. You need 1 quadrillion cells, right?
That's something that genomic stability took a long time. You want it as you do that, so you have to have durability, genomic stability, and then it needs to maintain pluripotency, meaning it can go into any cell type and you can drive it to become any cell type in your body. Importantly, in this case, pancreatic islets, right? That became our master cell bank. That sits in a freezer, actually a couple freezers just in case something bad happens.
Mm-hmm
that we can hopefully draw from for you know decades to come. That is, I think again, without speaking directly for regulators, any one of. We've had direct discussions with regulators in various parts of the world including the U.S., and I think broadly that we have alignment around the testing strategy and the release, and those are ready to go.
The second part to get is to manufacture this, to actually make the cells, right? That is a complicated process, right? Beause you're taking stem cells, you grow them up, and then you differentiate them into islets. Then you put you know make them into something that can be delivered to a physician, and they can transplant it. That we've done.
We've done it, we've moved it from a research scale and research reagents to, you know, a phase one scale with phase one reagents. We're in the process of tech transferring that into a GMP manufacturing facility. That's long pole number one. That's the most important thing we have to get done, or likely the most, the long pole to get the IND done. We're in the middle of that.
The second is we need to finish all the non-clinical testing, which includes just, like, things like GLP toxicology studies. When you transplant these cells into a mouse, do tumors grow? Like, we've done this many times. We've followed them for we've shown you data out 15 months. You know, it shouldn't happen.
We've done this we tested it many times. Biology you always breathe a sigh of relief when it's done.
Yep.
that one should be, you know, ready to go this year as well. Then you file your IND, and you get the study going, right? You obviously have to align on a clinical protocol with the regulators. Again, I think there we're at least at a pretty detailed level of have alignment with kind of important regulators around the world.
Perfect. Now, when the FDA is kind of looking at this, are they? You have as long-term follow-up as you can in non-human primate models and everything else. But do they still kind of worry, and do they try to ask you like, "Hey, if something goes wrong, is there a kill switch we can design? Is there any way that we can get rid of these cells?
Yeah
in case something goes wrong? How should we do it?
I can't speak for the FDA. I can speak for me. I worry, right?
Yeah.
I think we all worry. These are patients who, but for us, would otherwise likely live for decades, right? We have an enormous responsibility in doing something that is safe. To your point, now that we've hypoimmune-cloaked these cells from the immune system, we wanna make sure that they don't go awry, right?
Fortunately, I think one of the things we can say is like we've hidden these cells from the immune system, but not from ourselves, right? We went about kind of addressing this problem in three ways. One, make the risk as low as possible, right?
Mm.
That's partly about the genomic stability we talked about. You don't want cancer-causing gene mutations, and it's partly about product purity. You don't want other cells to keep dividing in your products. That's part one, make the risk really low. Part two, develop a system where you can detect something early if it happens, right?
Again, we've been working on ensuring that we have blood tests and things that can detect these things early. The third, get rid of them if it happens, right? There are three ways that we've addressed that. Number one, O ften these cells have been shot up through the portal vein into the liver, and they're just disseminated, hard to see, hard to cut out.
We're putting them in muscle, for multiple reasons, but one of them is because we can see them under imaging, and you can palpate them and that, and you can actually extract it if you need to. Like, surgically, that'd be relatively straightforward. The second is we've embedded a kill switch into the product, right?
On the same gene or plasmid that we insert the CD47 downstream of it, we put a known kill switch on that. We haven't disclosed what it is, but a person could take a generally safe medicine that's approved by the FDA, and it will turn on a process that will kill that cell.
Okay.
The third thing we've done, and this we've shown works in non-human primates and across multiple human cancer cell lines, is we've overcoming the immune response requires this overexpression of CD47. People have been making antibodies to block CD47 as cancer therapies unrelated to with this, for about a decade now.
We know that if we give those antibodies, that it will kill those cells, at least in every system we've tested. We've never done that in humans. We hope we never have to. We have, again, three pronged things. Make it least likely to happen as possible. Test the heck out of it, figure out how to detect it, and if you do detect it and it happens, get rid of it. We've tried to be really thorough about thinking about this. My real hope is that we never see anything.
You don't have to touch it. Yeah.
I do think, you know, just no different than any other cell or gene therapy product, there's a requirement to follow patients for 15 years, right, by the FDA. I'm sure we'll be following people for at least 15 years with this product.
I could talk to you about this for, like, the next hour. It's a fascinating program. You guys are the pioneers in this space as far as I'm concerned, and really hoping, you know, looking forward to seeing this in the clinic. In sort of the last maybe 40 seconds that I have left, I'd be remiss not to touch on the in vivo CAR T program.
Yeah.
There's been a ton of pharma interest, a lot of acquisitions that have been taking place on different platforms. You have a very unique platform compared to everybody else. Questions we get is, "Why is it unique? What's it gonna take for you guys to potentially be taken out or the platform to be in license since there's so much excitement?
Well, I'd say in this one, we made two fundamental bets when we started here, right? These are not consensus views. Number one, that cell specificity in delivery matters. By that, I mean only go to the cell you wanna go to. I think many people would say, "You know what?
No, you just need to get enough into the cell you're trying to get to. It doesn't matter where else you go." We would argue that it's important for safety, for immunogenicity, and actually for manufacturability, right? Since T cells are probably like one-tenth of 1% of the number of cells in your body, right? The second. Actually, less than that.
The second is that we've decided we really believe you need to have a signal that integrates into the target cell's DNA. The reason for that is we might make, call it 50 million, 100 million CAR T-cells, but you might be trying to take out 200 billion, 500 billion B cells and tumor cells, right?
That requires a multi-logarithmic expansion of the CAR T-cell. If you don't integrate, if you just stick a little mRNA in, progeny won't take the mRNA with it, so you can't grow them. As your cells divide, you lose the CAR part of it, right? Just becomes. They suddenly stop growing. Many of the acquisitions have basically been the exact opposite bet.
Good enough is good enough, and mRNA is a preferred therapy 'cause we think it might be safer, right? If it turns out that we're wrong on these mRNA and LNP will probably beat us, right? I think what we have the potential versus those to do is have meaningfully better efficacy, and much deeper remissions with cancer or in autoimmune diseases, right? Hopefully these will be curative therapies for people.
Versus other VLPs or virus-like particles, I think what you'll see hopefully is better tolerability and safety. We don't have time to get into why, but I think that's been seen pre-clinically, so we're optimistic that can happen. Now what is it? You know, what is this? We'll be in human testing.
We're optimistic it will work. We don't know it will. If it does, you know, what will it take for a partnership to develop or something like that? I don't know. I do think, like, Type 1 diabetes we'd be hard-pressed to partner this except in a really special situation.
One of the challenges of this in vivo CAR-T is it's a super competitive environment where we're going into. Forget in vivo CAR-Ts. B cell depletion more broadly, right? You got small molecules, antibodies, antibody drug conjugates, T-cell engagers, CAR T-cells, autologous, allogeneic, and in vivo, right? Having a really great development plan and execute on that very quickly is super important.
That may be something that we do, you know, can do on our own by being very focused, and may be something where a partner can help us move that more quickly. We'll be open to a partnership on that at the right time. I think human data is super important here. I think it will prove whether we have what we think we have, or that it's a bit different as it gets into humans.
Terrific. Well, I know we'll have clinical data, you know, hopefully at the end of this year.
I'm so-
We're looking forward to it. Steve, thank you very much for joining us here.
Thanks for having me. I appreciate it.