Welcome to the next session of the Guggenheim Oncology Conference. My name is Kelsey Goodwin. I'm one of the research analysts here at Guggenheim, now we are presenting with Sana Biotechnology. With me, I have the President and CEO, Steve Harr. Welcome. Maybe we'll just kick it off with a big picture question. With a focus on engineered cells, Sana is advancing two key platforms, the hypoimmune technology and fusogen technology. Maybe just walk us through these two platforms and how they each address known challenges in the cell therapy space.
Oh, yeah. First of all, thank you, Kelsey, and Guggenheim for having us, and thank you for joining us here in the room and also online. I think you probably recognize that we will be making forward-looking statements, take a look at risk factors in our K or Q filing. We spent a lot of time on those and try to make them really thoughtful, good place to go. The company has, you're right, we were founded under the belief that one of, if not the most important transformation over the course of the next several decades in medicine will be the ability really to kind of control cells and control their fate and then to modulate genes.
We try to really delve in and go after what we thought were the most important challenges to making that a reality. With gene editing or gene modification, or people sometimes call gene therapy, at the end of the day, you can pretty much do anything you want to a cell in a Petri dish, right, in vitro. The real challenge is doing it, you know, in vivo, in a human or even in an animal. That's because delivery to the right cells has been so challenging. We focused out of the gate on one aspect, is really trying to go after novel delivery technologies. The ultimate goal is to be able to deliver any payload, so, you know, be able to do DNA, RNA, proteins to any cell in a specific and repeatable way.
To be really clear, we can't do that yet. With the fusogen platform, what we're trying to do is do cell-specific delivery. With that, we are able to also deliver basically any payload, right? What we can do with a fusogen is pick a cell, it's called T cell, a hematopoietic stem cell, liver cell, we've shown all these, and we can deliver a payload specifically to that cell efficiently. Then you can put in, you know, maybe the CRISPR-Cas9 and be able to knock a gene. You can go in a gene-specific way, delivering a cell, the cells, you know, Sorry, you can change a gene in a specific way inside of a specific cell. That's the goal. It works. It works, you know, in animals.
We need to see what happens in humans. That's platform number one. That's the fusogens. The way that we approach that problem was we know that viruses can deliver payloads in a cell-specific way. As an example, COVID. You know, the coronavirus goes into cells that express the ACE2 receptor, right? HIV goes into CD4 cells, right? What we did was take a viral fusogen and engineer it, so that it will only go into the cell that we're targeting, right? I know you can get into how in a second. Then we put it onto a virus-like particle, right? You put in the machinery. That's basically how it works.
The other platform, the other side of it is instead of changing genes in vivo, was replacing cells that are too far damaged or gone, right? Building them from scratch. The whole challenge of transplant medicine from the outset has been rejection of allogeneic cells, right? You have to take every person who gets an organ transplant has to have profound immunosuppression. There's actually only one cell that we transplant, and that's red blood cells, right? There are millions of people. There, what we do is we've discovered a way to hide these cell, you know, allogeneic cells from immune recognition. It works. I mean, I think it's fair to say in a number of different preclinical animal models, including nonhuman primates, it seems like we've solved the problem.
What we need to really figure out is that translating to people, right? We'll know that over the next several quarters. Just to go back, the challenge of allogeneic rejection is you have to grapple with two parts of the immune system, the adaptive immune system, which is B and T cells. It's actually pretty easy to deal, right? People have figured that out. Unfortunately, so did cancers and viruses. We evolved parts of the innate immune system that will kill those cells if you're getting around the adaptive immune system. What we had to do is figure out how to really turn off both of them, and that's where people have failed to date. By the way, what we do, right?
We get rid of, you know, we disrupt beta-2 microglobulin, CIITA, which knocks out MHC class I and class II. We overexpress CD47. That's what red blood cells do. It's the only... That's not why we did it. It turns out to be true, and we did it, you know, we came at it actually from the paradox of pregnancy, right? And the fact what is the difference in the maternal fetal border, right? Where the mother doesn't reject the fetus despite the fact that it's half dad's DNA. It's also what red blood cells do. It's the only place you've ever had successful transplant.
I worry, I always have this thing in the back of my head, which is it works so well in nonhuman primates, but immunology has this funny way of humbling us. We'll get into humans, there will be about something we weren't thinking about. That, for me at least, that red blood cell biology is really reassuring. You know, we're, we have our IND cleared for the first drug. We'll have, you know, another one that we're testing with Type 1 diabetes shortly. We'll know this year, right, if this is really working or not.
Great
Long-winded answer.
No, that's a great intro. I guess we'll maybe dive into, as you said, your IND for your lead program, SC291, was filed. I guess maybe just walk us through the trial design and how this asset may be differentiated from competitors?
Yeah
... leveraging that platform you discussed.
We were recently just thinking about the CAR T space broadly and a comment. It's filed, it's cleared, you know, we're roaring to go. You know, what we've seen from the autologous CAR T-cell space has been really, I think, you know, encouraging and complexifying for us, right? The encouraging part is that, you know, it's really kind of growing, right? You're seeing them become a big part of the standard of care. They're taking on, you know, in second, third, even in the first line setting, established standards of cares across multiple different types of tumors and winning, right? They really are working. You know, and delivery and supplies still remain a big challenge, right?
That's all really good for us in coming in with this allogeneic. The hard part is, you know, the more they become established and more complicated, it makes our development paths 'cause physicians have alternatives, and patients have alternatives. You know, on the allogeneic side, you know, I think that generally the field's been disappointed by the outcomes to date. You know, personally, I think it was completely predictable based on the immunology. What we haven't seen yet is someone who can transplant allogeneic cells and have persistence of the CAR T-cell that looks like an autologous, right? CAR T-cell. I think if we do, you know, we have a chance to have, you know, as good or better data as autologous CAR T-cells. But you can supply it.
We already make it at a scale that's completely globally commercializable. The phase 1 study design is really looking at, you know, patients who have, you know, lymphoma or just anything but ALL, acute lymphoblastic leukemia. We're staying away from that here. The most important attribute that we will figure out very early is, number one, safety, right? And number two is, do the cells expand in a way that's similar to autologous CAR T-cells? 'Cause you will then see complete response rates, which you see in everything else. Then the most important element is just do the cells persist? You'll know in a couple of months after dosing this, because generally, you know, what's happening with allogeneic cells broadly is they're killed when their immune system is engaged, right? Within a couple of weeks.
Mm-hmm.
If we have cells that are around at two, three, four months, I, you know, personally believe we're gonna have a really important and impactful drug. What's beautiful about this is, you know, we have three clinically validated CARs, right? It's not just targets. The actual CAR itself has been in an autologous setting with something that looks like best-in-class therapy, right? That's CD19, CD22, and BCMA for multiple myeloma. That means that if we get this once, right? Where the allogeneic looks like the autologous, we have three drugs, most likely. Right? I just rarely seen that type of a risk profile, where it really comes down to our execution and capital, right? To be able to go forward. Because we have them, we make them, we've done the pre-clinical work, we know it works.
They've been in humans now. They've been in hundreds of humans, each of these CARs, right? You know, I think there's a lot of reason to believe that one will end up translating into multiple.
Mm-hmm.
You know, the most important thing to look at early, the trial design, just so I think people recognize CAR T cells, generally the FDA wants you to wait as you go through dose escalation about a month between each patient. You can see just to make sure there isn't, you know, some untoward neurotoxicity. CRS would take place in a couple of weeks, right? It takes a while to get through that. After it, just a couple of patients will know, I think, right? Either these cells are living-
Mm-hmm
... or they're not. Right? If they're not, you know, this didn't translate into humans. If they are, it's probably gonna translate, you know, not just even this allo things, but a whole bunch of other areas as well.
Mm-hmm. Okay, great. Initial data from that will be later this year.
Yeah.
Do you anticipate it to be kind of a focus on, PK and cell persistence, or will we see efficacy as well?
We will show you efficacy and safety data when we go to medical meeting. I, you know, we don't know if we'll have efficacy, but I hope we do.
Yeah.
I sure hope we do. You know, you start these drugs now at a dose where you should see some measure of efficacy even at the lowest dose, right? Which I think is the appropriate thing for patients. We shouldn't be giving them. If it's validated and safe enough, we need to be giving them something that has a chance of working.
Mm-hmm.
Yeah. Yeah, we'll have a good bit of data, by, you know, as we move through the year.
Mm-hmm. Got it. For the lymphodepletion, that's something where we've seen kind of a range for the off-the-shelf cell therapies. What lymphodepletion regimen are you-?
Yeah
... planning to use?
Our goal is to make these cells just like autologous cells, where your immune system does not see them. We will use lymphodepletion that is the standard lymphodepletion for an autologous CAR T-cell.
Okay, got it. Perfect.
Nothing enhanced. I can't imagine us going down that path.
Okay.
I actually think because autologous cells, people, like, people do get immune responses to them eventually-
Mm-hmm
... from the foreign elements of the in the CD19, the mouse portion of the CAR. That's why you see, I think when patients get redosed, there isn't that much efficacy or expansion. If this works like we hope it will, right? You won't even have that, right? You could see where we could even go with lower lymphodepletion than autologous cells. That's a dream. Don't expect that.
Next step. Okay. Maybe in the data next year.
Yeah.
Okay, great. As you mentioned, you're also advancing a CD22 CAR T with an IND on track for this year, I believe. Maybe just remind us how you think about CD22 as a target and why this might be successful-
Yeah
...on your end versus kind of some of the others that have pursued it.
Yeah. I've been in this CAR T world for about a decade, right? When I first entered, I had this belief that lymphoma, leukemia, and maybe myeloma should be just like hepatitis C. Completely curable for the vast majority of people from a very short treatment. You know, we weren't there. We started at the very beginning. It was a license, a CD22 CAR from the NCI. The goal was, we do know that some patients lose their CD19, or they get a splice variant where it doesn't have the epitope for the CAR to recognize, right?
The CD22 CAR that we licensed, you know, back in, you know, previous company was ultimately spit back out through all the mergers that happened, right, when Bristol-Myers Squibb bought Celgene. That CAR construct of the NCI has now been validated in over 100 patients who are CD19 refractory in lymphoma and leukemia with about a 50% durable complete response rate, right, across this. The way we think about this is, we went and licensed it, right? We went and licensed it 'cause it's sitting there at the NCI, and we have a CAR that's been validated in a, you know, a lot of people. We are gonna develop this for people who fail CD19 CAR T cells. That is, you know, a gigantic unmet need.
You know, as the CD19 population grows, it turns out still, you know, two-thirds of people don't end up with a durable complete response. Most people fail, right? You know, if there are thousands of people who are now being treated, that's thousands of people who are failing a year. The average survival of a patient who's failed the CD19 CAR T cell is five months. This is a huge unmet need with patients who really have nothing. You know, fingers crossed that this works like we hope it will because it will offer, you know, at least half of them a real lifeline that could be, you know, to get a durable, complete response or hopefully it turns into a cure. We'll go right into that population.
It may end up being the fastest drug to market that we have, just because the unmet need is so great that the clinical trial should be relatively straightforward, both to kind of move forward, and I think regulators will have a, you know, they'll be very thoughtful about the patients and how much they're suffering.
Got it. I guess, is the longer term plan here to only be post-CD19, or will you eventually wanna go into CAR naive as well?
I'd be pretty surprised. I don't think that CD22 is as good of a target as CD19.
Okay.
There's more variable expression, right? You can kind of see people who have low levels of expression don't respond as well. I think where you would really be interested is putting CD19 and CD22 together, which is what we almost did, but we didn't wanna making CD22 really work for patients who are in such dire need. Ultimately, when you put CD19. It's a little bit like HIV drugs, right? You know, when they first came out, you take one, people get resistance, and they take the second, and then they get resistant. You put them together, and nobody got resistant, right? The probability that you're gonna be resistant at the exact same moment in the exact same cell to both a CD19 target and a CD22 is very, very low.
That is ultimately where you wanna go, but we have to make sure we get it right, you know, each step of the way first.
Mm-hmm. Got it.
Like, we shouldn't rest. If we don't get to 80%-90% of people being cured, someone else will.
Yeah.
Right? Someone's gonna figure this out.
Got it. The third kind of prong in your CAR T, initial CAR T, strategy is a BCMA CAR T, which, like you mentioned, was in license and has data in the autologous space. I guess what were the clinical learnings from that program?
Yeah
...on the autologous side?
You know, we were developing our own BCMA CAR internally, and what's difficult is understanding how what you see in an animal will translate into a human. You know, we found a company, IASO, that has now dosed 100 people at the BCMA targeted CAR T, and they have really kind of best in class data. They've gone even into CAR failures. They have 95% of the patients they treat become MRD-negative, right, immediately. That's the best predictor of long-term durable responses. At one year, 80% of them are MRD-negative, right? It's very consistent with, I think, what you've seen from the best kind of commercial CAR T cell.
It's 100 people, and that 80% includes, you know, almost 15% of the patients had already failed another CAR T cell. It's a trial that was run outside the United States. The patients had gotten less daratumumab than the U.S. population would. That's like, you know, he's like, you know, that could make it a little easier for and raise the efficacy. That MRD negativity is such a great predictor. What we've learned is, first and foremost, it's safe. Right? I think that's a big deal when you're starting with a new... The second is, it really works, right? I think the allogeneic CAR T cells in BCMA have been more disappointing even in CD19.
That may be because persistence is more important in myeloma, and it may be because the CARs weren't really quite as good, right? Because we don't really know, like. Here we have a validated CAR construct. If we get the persistence right, again, I think we can really do something important there. So we've learned a lot through the human data. It's a very impressive data set.
Great. Like you said,
It's not ours, by the way.
Okay.
It's other companies. Yeah, no, we're not making that drug. That's in the autologous setting.
Yeah.
We have the actual gene construct.
Right. validated CARs-
Yeah
some, initial proof of concept clinical data.
Yeah
...CD19 later this year. Shifting gears to some other programs you're working on. You also are planning to file an IND for primary islet cells, for Type 1 diabetes.
Oh.
Maybe remind us, a lot of us are focused on the cancer space and can't really comprehend how big Type 1 diabetes even is.
Yeah.
Remind us of the commercial opportunity and unmet medical need in this setting.
Type 1 diabetes is just the immune system knocking out the patient's islet cells, right? The patients suffer a lot because even with best therapy today, they have a 15-year shorter life expectancy. Often they're, they have blindness, amputations, kidney failure at the end. If you have to manage it through your whole life, you're constantly every minute of your life is changed, right? When it happens. You know, with the field figured out how to transplant cadaveric primary islet cells, right? With very significant immunosuppression. It's been done thousands of times. It will get a patient to be, have euglycemia with no insulin, often for a decade, right? I'd say at an average, call it five years or so, and they might need to do it again.
The hard part is most people just can't tolerate the degree of immunosuppression that's necessary. There isn't, it hasn't grown that much. you know, others have shown that you can take a stem cell and make an islet cell and transplant it. A patient, again, with immunosuppression can be totally normal. Our goal is to make, to put this hypoimmune technology that's in the T cells into a stem cell, grow it into an islet cell, and transplant that into a patient. One treatment, you know, normal glycemia, no insulin, no immunosuppression for life. That's the goal. We've shown in basically every preclinical model that we can overcome both allogeneic rejection, right, and also the autoimmune rejection of Type 1 diabetes, which we can get into. Really, the question is does it work in humans?
making a cell, a stem cell-based product takes a long time, right? what this study is, a team came up with an idea of going to one of the centers that does primary islet transplants, doing these gene edits, right? transplanting them and see what happens with no immunosuppression. we'll do that this year. you'll know. I mean, if it works, to me, in my mind, what happens is a cure for Type 1 diabetes moves from being possible to being entirely inevitable.
Mm-hmm.
Like, it will happen, and it will happen this decade. Right? It may not be us, we could screw it up, but someone will do it. That is what's so exciting to me about this. You will know this year is a cure for Type 1 diabetes inevitable. Because you'll know, like, if a transplant immunologist would tell you, 'cause you're putting this into someone who's got, you know, a revved up immune system, not even immunosuppressed, if you use transplant cells, they're gone in about a week. If they la-- there's nothing that's coming back, right? If they last a few weeks, there's nothing that's gonna get them later, right? After 2, 3, 4 weeks, you'll be very confident.
Like our, the person who runs the program for us said if they're still there at 2 weeks, he's opening a champagne, right? you know, there's a they may not be stairs. You know, is that, you know, it you'll know pretty quickly if it works or not. You know, again, it's a riskier setting. The T cells, we've got a lot in our favor. You've got from the immune perspective, right? It's where the patients are gonna get lymphodepletion, which decreases their immune system. They've got cancer, which beats up their immune system. They've got a lot of different chemotherapies by the time they get to us. We're first targeting CD19, which knocks out B cells. They don't really make antibodies. Like, the deck's stacked in our favor in a lot of ways.
Yeah.
You go into Type 1 diabetes, and the patient not only has, you know, allogeneic rejection, but they have T cells and antibodies that are geared just to that cell, right? Because they're autoimmune. We have a lot to overcome. You know, but it works in animal models, so hopefully it will translate to humans. That's a group of people who could really benefit from a new therapy. What's the last thing, the thing that really gets the clinicians incited is insulin was first used in humans in 1923. Their goal is on the 100th anniversary to have the next therapy ready, right?
That's great.
Yeah.
I guess with potentially seeing initial data this year from that, I guess you kinda spoke to it a bit, but what would be considered a win? What are kind of the key PD and efficacy readouts that would validate this in your opinion?
We know that primary islets work. The key for me if it went. We'll start a lower dose, and it may work. The most important thing to see is do the cells, is there immune response or not? Do they live?
Mm-hmm.
If they live without an immune response to them, that is a win, right? That's the most important question. You know, at this dose, the second win that could happen is that patients have stable and detectable C-peptide. When insulin's made, it's made as proinsulin, and it's cleaved as it's secreted into our blood, and you have insulin and C-peptide. If you see C-peptide at a stable level, you know you're making insulin, right? and if that's happening, the patient will have a lot of benefit from it.
Mm-hmm.
The third is that they actually, you know, have better glycemic control, right? They don't need-- if their best would be off of insulin. You know, we'll see at the doses that we start if that's possible or not. We're gonna start with the main goal being understand the immunology 'cause we can, we can always get the beta cell part right? That's the easy part. The hard part's the immunology.
Okay, got it. Then maybe, we're running out of time, but one quick one on your lead, fusogen program, the in vivo CAR T-
Yeah
IND on track for this year. I guess how is this program differentiated and how do you think it will be positioned longer term?
The beautiful part of the in vivo CAR T-cell is you get... You asked the question. It's a single injection. There's no lymphodepletion possible, right? We have to have T-cells there to actually transduce, right? You can't have them go away. I think the ease of use, it'd be a single shot, and there'd be no chemotherapy at all. It'd be completely off the shelf. I think if it really worked well, it would be what people prefer, right? I think biologically, it's a bigger hurdle, right? I mean, it's really straightforward to get this allogeneic thing to work. We know exactly what needs to happen, right? We know exactly what the risks are. We know exactly you can...
With, you know, you're going in here, first we have to get, you know, we have to be able to deliver enough cargo to T cells safely. That's part one. We just do that. You know, that will be in a phase 1 study in my mind success, right? The second biology hurdle is you gotta get the cells to grow and expand without the cytokine support of lymphodepletion. If that happens, we'll be thrilled. We just don't know if it will or not. You know, We're able to deplete B cells in nonhuman primate models, so It's possible, right? We really wanna see, do you need cytokine support? We're ready if you do, but we'd prefer not, right? The third will be, do they stick around long enough that you see durable, complete responses?
We start with you gotta get the first part right or you can't learn 2 and 3, and those are bigger biology hurdles than the allogeneic. bigger biology unknowns, I should say. We know exactly it. In allogeneic, it's all known unknowns, right? I think here we have some unknown unknowns just 'cause no one's done this before.
Right. Got it. Okay. With our last 30 seconds, I think we're a little over, but maybe just remind us cash runway and expected catalyst lineup for the next 12, 24 months.
Yeah. We ended the Q3 with just over $500 million in the bank. We said that's enough money to get us into 2025. You know, we'll need more money, you know, over the next couple of years. We will you know, have the opportunity to really understand these drugs before we need to do that. You know, I think the most important elements with. You'll know this year from two different studies whether or not this hypoimmune platform really works. You know, in the case of the allogeneic T-cell platform, it will translate directly into very, very clear efficacy with the scaled manufacturing process that we're just running, right? In the case of the beta cell, you know, we'll translate into hopefully a scaled beta cell that comes from stem cells, and that...
We still have work to do to really, you know, get that to a place where it's ready to be at the scale and consistency that will, you know, be globally commercializable.
Mm-hmm.
Right? That one still has some work. It's so... That's the exciting one to really be able to go after.
Yeah.
You'll know both those answers this year.
Great. That's great. We are out of time here. Thank you so much, Steve, for joining us.
Yeah. Thank you, Kelsey.
Thank you everyone in the room for joining us, and I will see you at the next session.