Good afternoon, everyone. Thank you so much for joining us. We are really pleased to have Steve Harr, President and CEO of Sana. I'm Salveen Richter, Biotechnology Analyst at Goldman Sachs. Steve, before we jump into the programs, can you just provide us with a quick overview of your ex vivo hypoimmune and in vivo fusion platforms, and discuss how you're differentiated in this field of cell therapy?
First of all, thank you for having us. It's great to see you and thank you for joining us, both on the webcast and in this gray and dreary Southern California day. I mean, we don't have many of those. Thank you for joining us in the room. I think, as you probably know, we'll make a few forward-looking statements.
Sure.
Please do peruse our Q for risk factors and things like that. I, you know, just as a way of background, you know, we believe that one of the most important transformations that will happen in medicine over the coming decades is the ability to modulate genes and use cells as medicines. Our goal is to build, you know, one of the leading companies of that era. As Salveen mentioned, we started the company really around two platforms, really going after what we think are some of the most important challenges in making the vision a reality of cell and gene therapy. The first is the hypoimmune platform, as we call it. The goal of that is to hide cells from, allogeneic cells from immune detection.
There's been some progress in cell therapy. I think everybody recognizes autologous CAR T-cells are a great example of something that's having a meaningful impact, and we should likely see something with HSCs and others going forward. You know, the challenges have been that, one, there aren't that many cells where you can actually make autologous cells out of. They have to exist in suspension. When you can, it's a complicated and expensive process that has limited access, right? Our goal is to make cells from a single source, or from a aggregation of sources, make genetic modifications to hide them from immune detection, be able to transplant, for example, my cells into you, so that you won't reject them. That will give us the opportunity really to do two things.
One, build medicines that we think can be at a comparable or better efficacy and safety profile and have scale compared to autologous cells. To go after cell types that autologous cells can't do. That's probably even bigger. That's what we're doing. The way that we approach this is, if you look at immunology, there are two aspects of the immune system you have to deal with. One is the adaptive immune system of B and T cells. It's actually relatively easy to deal with through genetic modifications. You then have to deal with the innate immune system, natural killer cells, macrophages, and that's actually been really the challenge for the field. We're really pleased with the progress we've made. We do three gene modifications.
It turns out that's much simpler than we thought it would be. We've shown now in non-human primates, in over 40 different animals, in humanized mice and mice, that we can effectively prevent immune recognition, immune and we have immune evasion. I would postulate to you that if you were a monkey or a mouse, we'd solve the problem of allogeneic rejection. The critical question, which I'm sure we're going to get into, is how do these data translate into humans, right? We'll know that in a matter of months. Then, you know, then it will just be, you know, how quickly and efficiently can we move that into a number of different therapeutics, which we can go through. That's the hypoimmune side. I'm we're super optimistic about where that's gonna go.
If it turns out we have hidden cells from the immune system, it's a pretty straightforward path to making, to really having, you know, three different large categories of medicines. One are allogeneic CAR T-cells for blood cancers. We'll target, we have three different targets. One would be allogeneic CAR T-cells. Second would be allogeneic CAR T-cells for autoimmune disorders. Then a bit harder, but where we've made a lot of progress, is stem cell-derived products for type 1 diabetes. All three of those, I think, are areas where we're really pretty or very excited. The other platform is the fusogen platform. The idea of this is just to have a look at the field broadly. You can more or less do anything you want to a cell in a petri dish. The challenge has been delivery, right?
There's been some progress in delivery, particularly to the liver, but it's been very difficult to get into other cell types. The idea here is to do cell-specific delivery, which is both better from a safety and efficacy perspective, most likely, and also better from a manufacturability, 'cause the vast minority of cells are gonna be your target cells in any scenario, trillions and trillions in our body. What we've done is figure out how to package in the gene editing or base editing or prime editing reagents so that you can do gene-specific modification in a cell-specific way. The first IND around that platform, you know, will like, hopefully be in later this year. I think it'll take us into next year to figure out how well is it really working.
If we can do that, we think that that can offer a lot of promise. I'm sure we'll get into that. That's basically the idea. The way that that program, that that platform works is viruses have figured out a long time ago how to get into cells, and we hijack some viral mechanisms to do cell-specific delivery, and you have to modify them. Then we've hijacked the innards of a virus to become like a virus-like particle, so it no longer delivers the viral proteins and DNA and RNA, but what we put in there, and then we can scale the manufacturer. That's a little bit how it works.
Great. Steve, you talked about how we're going to get first proof of concept, you know, in a couple of months, and this is really from your lead asset from your hypoimmune platform, where we're getting phase I allogeneic CD19 targeted CAR T data in B cell cancers. As we think about this data set that you're going to provide us, clearly the target's validated, so we're really going to be understanding your platform. What are these efficacy measures and safety measures that we'll be able to look at to assess this?
Yeah. A really important question. What we chose to do is take a step back. Believing that you can overcome immune rejection of allogeneic cells is a pretty big biology step, right? What we decided to do out of the gate was, you know, you have kind of four big risks in drug development and making a platform. Platform risk. Does my platform work as I think it will? Disease biology risk. Can I intercede important biology? Drug development risk. Can I see it and actually be able to prove it in people? Commercial risk. Do I really need an unmet need? Was to go and really figure out an area where we could isolate the platform risk, and if we truly did what we thought we did, we'd be able to intercede an important biology.
We knew exactly how to prove in humans, and it'd be important commercially. The CD 19 CAR T cell. Actually, the beautiful part of this is we can peel back the layers of, I would say, efficacy or proof, very quickly. The most important question, I think, is if we have solved allogeneic rejection for non-human primates and mice, does that biology translate to people, right? It turns out that's actually really easy to find out. We, when we make these drugs, let's say Salveen's the donor. We take her white blood cells, we isolate T cells, and we gene modify them. There are five gene modifications that we do.
When you and then we grow it up and infuse it in the patients, you know, we can talk, we can make a lot of doses from that, but only about half of the cells will have all 5 gene edits, right? That's a bug, right? It becomes a feature in understanding our drug because we're gonna. When you give a CAR T cell, you lymphodeplete, you knock out a lot of their immune system, and it comes back over about two or three weeks, which means at one month, if this really works like we think it will, what you will see is that all of the cells that are not 100% gene edited will be gone, and you'll be left with 100% gene edited cells.
You want to see that maybe over a few months in a few patients and things like that. If you see that, you know for sure that the data we've seen in animals, which is that we've kind of dealt with immune rejection, translate to humans. That doesn't mean we have a great drug, but it means we have a spectacular platform that's going to be broadly applicable. To really understand if the CD19 then is a good drug, what you want to see is, hey, can I get patients into complete response? The first level of evidence would be that the cells persist for a while. I think the data are very clear. You need, I don't know, three to six months.
These CAR T cells need to stick around that long to really have that kind of a profound benefit in cancer patients. The second layer of evidence will be. First layer of evidence, cell enrichment. That's a great day. That day, if we have it, we will change the way we invest internally because we will know the hypoimmune platform is going to translate. The second will be, do you have a high level of complete responses with cellular persistence? That will tell you if you have a great product. There will be people who want to see... By the way, we'll know the first soon, the second, you know, we'll begin to figure that out this year. The third is, do you have durable, complete responses at a high level?
That will take us, well, in the next year to figure out, different people will probably have different views around, you know, what they're willing to accept. If you have it, you know, what you have is we have a scaled process, right? This process, I would say, the most likely dose we can make commercially, doing nothing else to what we do, about 450 doses per manufacturing run today for cancer and about 950 doses per manufacturing run for we think will be the autoimmune dose. It's immediately at a scale that we don't have. It's very de-risked. If it works in CD19, first of all, it will probably work in CD19 in autoimmune disorders. Right?
That will be, we'll have to figure out exactly where and how. You get CD19 in cancer, then you get CD19 in autoimmune disorders, and we've licensed in the only validated CD22 CAR. Right? It's likely going to work in CD22 because there's not much, there's no risk. It's just capital execution risk. The biology risk is kind of out, and it's likely going to work in BCMA. We've also licensed in a validated CAR in the autologous setting. From a single experiment, you can de-risk four separate drugs, right? That's a very rare opportunity. It will be daunting for us to execute on that, and it will be expensive to execute on it, to be very clear. We won't be able to do it alone, but that's what we get out of those proof of concept studies.
Steve, maybe you can frame for everyone how you would position this?
Say again?
How you would position this drug in the CD19 market if you were to be successful? Like, how does it, you know, play out versus all the existing therapies, the autologous therapies?
First off, I think the data from the autologous CAR T cell space has been really good, both for CD19 and BCMA. I think in CD22, what they have is really good. The companies continue to make progress, both in terms of expanding their labels and in being able to manufacture the drug. How we will position it will depend upon the data, to be frank. I think what we have is a drug that, first of all, is available today. Right? It's not available in 30 days, not in 14 days. You don't have to go find, the doctor doesn't have to find a plasmapheresis site and a slot. I think people underestimate the complexity of all of the autologous supply chain, right?
From a provider perspective. It's available today, it's off the shelf, and, you know, if it looks as good or better, which is what we hope, as an autologous CAR T cell, we'll have a couple of things we can do. We can get a broader label. We can go into places like CLL, where it's been very difficult to manufacture the drug. We can go into places like ALL, where it's been difficult to bridge patients through the manufacturing process or timelines, and we can go into non-Hodgkin lymphoma that is available. It will take time, though. I mean, the companies are generating very good data in the second line, they'll have it in the first line. These are big markets, and it's available.
I mean, just the biggest position will be, it will be available for your patient, it's available for your patient today, right? It's available everywhere you'd want to use it. My hope is it will be better, and that makes it way easier to position. You know, we'd like to be at least the same, we'll have to see. The data will tell us.
Let's pivot to your second program from this platform, which is SC451 , which is an iPSC-derived islet cell program or asset in type 1 diabetes. You're gonna file an IND this year, but there is an investigator-sponsored trial utilizing your platform to modify islet cells here. Help us understand how this program versus your program differ, and whether we could look at this program and get some sense of proof of concept for yours.
By the way, just to be clear, I mean, it's the second area. The allogeneic CAR T cell platform will have a lot of INDs coming in the very near term. Just, you know, it will be before some of the SC451 stuff. If you just move on from the allogeneic CAR T space, we have those four different near-term opportunities. The next exciting area to take this platform is type 1 diabetes. Type 1 diabetes is most simply a immune rejection of the patient's pancreatic beta cells, right? They no longer make insulin. 100 years ago, it was a death sentence. In 1923, there was the invention of insulin, and now patients do reasonably well, but they don't do great, right? It's still a real challenge.
Surprisingly, if you look at the data, glucose control has gotten worse over the last decade, not better, despite all of the, you know, real-time monitoring interventions that exist. What we know, first off, for about the last 15 years, it's been possible to isolate cadaveric islets and transplant them into patients with immunosuppression, and patients can be euglycemic with no insulin, but with significant immunosuppression, right? For five, 10+ years. Right? Published in the Journal of Medicine, other places. Not scalable, difficult to replicate, right? Hundreds of patients get this treatment per year. There aren't that many people for whom lifelong immunosuppression is better than lifelong insulin. We now know from others in the field that you can make a consistent product from stem cells, right? That can have a similar short-term benefit.
What we don't know is, can anybody figure out how to overcome immunosuppression, right? The autoimmune and allogeneic rejection of cells. If you can, you can now put all the pieces together, right? You can make a long-term product at scale, where a single injection will leave a, hopefully, a patient euglycemic off insulin for years. Our goal of the product, SC451 , is to take pluripotent stem cells, gene modify them, grow them up into islets, transplant them simply into the arm, and have a patient who can just go about life normally for a long while, a person, no longer a patient, right, for years and years and years. What we're doing is, that's a hard thing. That will hopefully have an IND next year. That's our goal. Our goal was this year originally.
It's just, it's a lot of work to gene-edit stem cells and control the product turn. That's doing well, though. What we decided to do is to try to learn the immunology in the short term. We're taking cadaveric islets, or the investigators are. A person dies, they get the pancreas, they isolate the islets, just like they do for the normal transplant. They then gene modify them. They put these gene edits in, and we will transplant that into a person. The goal is to see that these cells survive without any immunosuppression. If they do, you will now have checked all three boxes of making a scalable product, right?
A cure for type 1 diabetes moves from being something that's kind of possible to being something that's inevitable. It's completely inevitable, and it will happen this decade. We may not get it, right? I mean, that's, you know, there's a lot to do, but it will happen 'cause all of the boxes have been checked. We're actually quite optimistic about that. It's a CTA, not an IND. It takes place. This study will take place in Europe. Our goal is to be able to transplant and get the data this year. And, you know, things are on track for that.
What do you think we could understand from this readout? Like-
Good yeah.
What should we be looking for in this data set?
Yeah
What could we understand from that?
Yeah. you could get it's kind of peeling back the evidence of, the onion of evidence, I guess. From our perspective, the most important question is, do the cells survive?
Yeah.
Right? You can see that in an MRI, are the cells alive. As you look at if you just transplant allog, you know, allogeneic cells, or if you were to transplant an autologous cell in a patient with an islet in a patient with type 1 diabetes, they'll be dead in about one week, right? Not the patient, the cells. We see cells surviving at two weeks. Like our immunologists say they're popping the champagne. I ask them just to have a beer and maybe champagne in one month. That's really what we're looking for, is cell survival. The easiest way to see that to the lowest bar is MRI. Right?
The next best way to see that, and I would prefer to see this, is when a cell makes insulin, it actually makes proinsulin, right? It secretes C-peptide and insulin. A type 1 diabetic has no C-peptide. You know, those of us who don't have type 1 diabetes all have it. If you see stable C-peptide, you know you've overcome immune rejection, and the cells live. That would be the second best. That would be next best. The next best is actually seeing patients not need insulin, right? We're unlikely in the first dose in the first patients at a dose well, that will happen, but it's not impossible. It doesn't really matter immunologically and from a learning perspective around what we have, but I think it's more interesting and it's better for the patient, obviously, if we get them off insulin.
That would be how we think about it. Look for immune evasion by radiography, then look for the biomarker C-peptide, then look for patients not needing insulin, exogenous insulin. Those are kind of the three levels of efficacy.
Vertex has two platforms.
Mm-hmm.
Their hypoimmune platform and their ViaCyte platform with data sets that are starting to read out. How does your program differentiate itself from those two platform programs? What are the learnings you can take from their data that de-risk your program?
Yeah. First off, I think they're wonderful companies, and I really spend almost no time worrying about them. We do try to learn from them. I always just take the step If we somehow figure this out and it works, and then we figure out how to scale it, and we can make 100,000 patients of drug per year, and we dose 100,000 people for a decade, and no one ever needs to be retreated again during that time, we will have only treated 20% of the people who need these drugs. Like, competition is just We need it, right? It's, it will be good for the field. We are approaching problems in different ways, and I think that we can probably learn from each other.
You know, first off, just the fact that they're in humans, I think it's been really great to see that a stem cell-derived islet can lead to such, you know, great benefits for people. We do a few things differently. Number one, the goal of our gene modification is completely evade the immune system and not need any immunosuppression or any devices. Hopefully that works for people, they're approaching it a different way. The second is we put the cells in the body in different places. They're going through the portal vein into the liver. We're gonna go into muscle. More people have been dosed in the liver. I'm sure that's why they're doing it, and that makes sense. You know, there are challenges in the liver.
One, the, you know, injecting through the portal vein is an interventional radiology procedure. It has complications, and it's not as easily scalable. Two is when these cells go in the liver, they immediately undergo something called IBMIR, immediate blood-mediated immune response, and you lose a very large percentage of the cells. That's one of the gene edits that CRISPR is making, is trying to get around that. We just go in the arm. It doesn't happen there. It's more scalable going in the arm. It is more... You know, we think cells will survive better, and the physiology seems to work just as well in patients who have received it with cadaveric islets. There's a lot that's different. The edits we make, the type, you know, the cells. I'm sure the process is different.
I'm sure the cells are a bit different. We don't really know what each other are doing.
Okay.
We root for them. We really learn from their successes than their failures.
You talked about with allogeneic CAR T, the CD22 program here. How would you study this target? I guess, where would you position it in your trials, and then?
Where we what?
Where would you position it?
Yeah
your first in-person trial?
Very straightforward. I got to know the CD22 target about 10 years ago. You know, it just seems like these lymphoma leukemia should be a, you know, most like hepatitis C, single treatment, you know, more or less curable for the vast majority of people. Maybe we're going to get there with myeloma. It's getting more, you know... It's pretty clear that at least in some patients, either there's an immune response to the CD19 CAR, or you have a loss of the CD19 antigen. Right? It's an escape mechanism, and patients fail. So we actually, we, in a different company, we licensed this drug, this target, and it was kicked out through a series of mergers, and it's back at the NCI.
This CAR has been validated in around 100 people in CD19 failures in lymphoma and leukemia. We licensed it for allogeneic in vivo use, and the positioning will be in people who failed a CD19 therapy, a CAR T-cell, you know, or maybe a bispecific, right? Because those will be important as well. Pretty straightforward. That market is just going to keep growing as both CAR T-cells and bispecifics grow. You know, about two-thirds of patients don't have a durable long-term complete response, and they have an average survival of around five months at this point, if you fail the CD19 CAR. It's a really big unmet need.
We'll have an off-the-shelf therapy, hopefully, that is very effective, we'll have to see, for them in that field. Where does it go? Right in that field. Just patients who failed other therapies....last line. It's very straightforward. There are a lot of patients, there's nothing for them really today, that actually could be probably become our first drug that's ever approved, just 'cause it's such a straightforward place to develop the drug. If you were to draw the perfect timeline for both CD19 and CD22 today, they end up right on top of each other.
You hosted an R&D day recently. What were the key points you wanted to get across to the investor community about the company as a whole? You also talked about the autoimmune disease.
Yeah
-effort utilizing CD19, and you mentioned how translatable that is, but we really haven't seen too much on CAR Ts in autoimmune. Help us understand why you see that kind of direct line to translate.
Yeah.
Yeah.
I'm gonna address that one and come back to the R&D.
Sure.
'Cause one of the key points we really did want to get across at the R&D day was the opportunity for the field, and in particular for Sana, in going after autoimmune disorders with the CD19 CAR T cell. This is something that has been we've wanted to do for a long time, right? It's pretty straightforward. If you just take a big step back, the industry spent about 30 years trying to figure out where to go and where B cell depletion derives a, that leads to a clinical benefit. There are probably about, if you look across oncology and autoimmune disorders, there are over 80 diseases where there's been some evidence of efficacy. It turns out the CAR T cell is the greatest B-cell depleter man's ever made, right? Or humans ever made.
That's kind of where we want to take it. The challenge with autologous CAR T cells has been twofold. Number one, every time you move into a new disease, you have to redo your process, right? You have to prove to regulators that you have a stable and controllable drug. That makes it hard to move across diseases. Two, it's just a scale problem. We have, just from for phase I studies, plenty of drug on the shelf to figure this out. Really, what really jumpstarted this was data last August, September, that was published in Nature from a German group in lupus nephritis. If you haven't read the paper, it's like every time I read it, I find another thing that's just so spectacular for these patients.
You now have these patients are completely off therapy, the longest patient's out over two years. Every single physiologic parameter is normalized. Every single biomarker, like double-stranded DNA or ANA antibodies that you use to look at lupus, have totally normalized. I don't think you're gonna see that this works in 100% of people as you go to broaden it, but the data are just you know, really interesting. It's worth reading. That same group has shown that not only does this work in lupus nephritis, but it works now in scleroderma, a giant unmet need, and in myositis. It will likely work in a whole host of other areas.
What we can do, because we have the drug product, is actually go right into, you know, maybe there's a small dose finding portion, and then run a basket study across multiple indications. You can then, as we get signal, really just go into broadening them towards like registration type studies, depending on what it is. That's an opportunity we can process near term, and we were very fortunate. It's not why we went and hired him, but we brought in Doug Williams as our Head of R&D. If you know Doug, he was the Head of Research at Immunex. They developed this Enbrel very broadly. He then was Head of R&D at Seagen.
He actually ran R&D at Biogen as they went through both Rituximab and Ocrelizumab and other things. He's someone who's steeped in immunology, understands the drug development paradigm here. I think you can actually move very quickly, and because of the manufacturing, instead of you asking us how we're gonna position this versus autologous, you know, we'll be able to beat them to the market, potentially in some areas at least. We're really excited about that opportunity. It's gonna be harder than what the Germans have shown it today, 'cause I can't imagine that it's such a perfect drug.
We'll have to figure out the right patient populations and things, but it's one where, you know, there's no reason to believe that CAR T cells can't be as big in autoimmune disease and as transformative for autoimmune disease patients as they have been in hematologic malignancies. In fact, they'll probably be bigger. That's was one thing we wanted to get across. We don't have a lot of time left-
Mm-hmm.
I'll let you figure out where you want to go next.
I just want to touch base on the fusogen program and platform.
Yeah
Where we will see that first proof of concept? I know you've incorporated-
Yeah
A second-generation manufacturing approach to increase potency, but help us understand how you de-risk that platform?
Yeah. Fusogens are super exciting. Again, you can do gene-specific modifications with cell-specific delivery, right? The first program in humans, we'll be looking to deliver the DNA to make a CAR into a CD8- positive T cell. We'll, you know, hopefully have an IND later this year. Last year, we took a step back because we had a, you know, you've mentioned improved manufacturing process. We improved yield, purity, and potency, right? It's about 55x improvement. Just to put that into context, we put more medicine now into 7 cc than we used to put into 1 liter.
Wow!
Right? It's, like, it's a true game changer from what we have as a drug product. It turned out that as we did that, we got 2x or 3x improvements as well, in how well it worked in T cells, right? It became just something we needed to do. First program will be in T cells. We'll figure it out as we move through next year, how well that works. What I really like is, these are things like HSCs, where you can deliver the gene editing or base editing or whatever machinery, directly to hematopoietic stem cells. We've shown we can do both. It will, you know, take a few years to turn that into a drug that's ready for human testing. It's a, it's a process, right, to really do this.
That's one where, if with proof of concept, you can see a single shot, no lymphodepletion, an opportunity to really go after a whole host of areas. First, where we already know that fixing the genome works, then we'll go after other areas. That's coming at us quickly.
Great. Well, with that, thank you so much, Steve. Really appreciate it.
Thank you. Really appreciate it. Appreciate the time, the audience as well.