Thank you, guys, for joining us. I think we're running meaningfully behind. Steve, great to have you here. I always talk about this. You were the first presentation at the first conference we started, so I always look forward to this chat. I'll let you kick things off.
Am I going to get any questions from you? I just get to roll for a little while. I love it, so thank you, everybody, for joining us, and thank you, Umar, for inviting us down to the conference, and so for those of you guys who don't know Sana, we're about five or six years old. We started with the goal of trying to build one of the more important cell and gene therapy companies. We had two goals as we set out the company. One was to really kind of figure out how to overcome the problem of allogeneic rejection, meaning you put cells into you, you'll notice them as foreign and try to kill them, and in doing that, we were optimistic that over time we could solve some of the problems of scalability and reproducibility that have kind of bedeviled the cell therapy space to date.
And the second was to be able to deliver genes and genetic material in vivo. You can do more or less whatever you want to a cell on a Petri dish, and the hard part is to do it in a cell. And the good news is that we've made really meaningful progress around both of them. And I think scientifically things have gone quite well. It's taken us a bit longer than we hoped to get some of these things done, and that's always a bit challenging, but I think we now sit on the precipice of some really important human data. Probably the place that has the most excitement around what we're up to on the cell replacement therapy is type 1 diabetes. And type 1 diabetes is a disease where the immune system knocks out the patient's beta cell, and they can no longer make insulin to respond to glucose.
It's been known now for several decades that you can take a cadaveric islet, or it's a cadaveric pancreas, isolate the islets, and transplant that into a type 1 diabetic, and they will do amazingly well frequently for decades now. The challenge is that that's neither a scalable or reproducible supply source, and there aren't that many patients. They have to get immunosuppression like a transplant, like an organ transplant. There aren't that many patients for whom lifelong immunosuppressions but are lifelong insulin. Others in the field recently have shown that you can take stem cells and grow them up into islets, and that that is a much more reproducible and probably scalable supply source. Again, though, the patients have to be immunosuppressed. They have that challenge. There aren't that many patients that can do this.
So very shortly, I use the word soon, we'll have human data where we are gene modifying cadaveric islets. This isn't our primary drug. And we can understand, can you now get rid of all of the immunosuppression? So a patient will be dosed with an islet in their arm with the goal of seeing them make their own insulin with absolutely no immunosuppressive drugs. And if that happens, I think you can safely say to yourself that a cure for type 1 diabetes has become inevitable. I'm optimistic we'll be one of those that do it or maybe the company that does it. We may not. We could still slip up, but it has become inevitable. And so at that point, I think you can feel really excited, particularly if you have friends and family with the disease. We have a couple of other programs in human testing.
And by the way, our goal there is to take a gene modified stem cell. We modify it so that the immune system won't recognize it, grow it up into a pancreatic islet at scale, and then transplant into a patient's arm. So with one therapy, hopefully they have normal blood glucoses with no insulin and no immunosuppression for life. That's the goal. We have a second program in B-cell mediated autoimmune diseases, things like lupus, vasculitis, multiple sclerosis, myasthenia gravis. And I think many of you recognize that 20 or 30 years ago, the only way to treat these diseases was with a sledgehammer. You basically knocked out the immune system, and the treatment was often as bad as the disease.
Really, with the advent of the TNF inhibitors, we were able to go after single cytokines, and they've become the largest classes of medicine in our industry, largely related to being able to turn off a portion of that immune response. Unfortunately, many patients are taking these drugs for a long, long time with a lot of toxicity. And over the last few years, it's become clear that you may be able to completely reset the B-cell repertoire with a CAR T-cell or something like that, and that a patient may have something like curative intent from a single treatment, no therapies, and hopefully a normal life going forward. And so we have a CD19- targeted allogeneic CAR T-cell that's in phase I studies for those B-cell diseases, and we'll have data in 2025. So those are probably the two areas people focus on the most.
We can get into other things we're doing in a minute, but I think I'm taking up a good bit of our time.
No, no, that's great. Maybe, Steve, can you just reorient us first? There's some programs you guys strategically refocused on. What were the learnings from that, and could you remind us what those programs were?
Yeah. So this was not that long ago. So we had a couple of things. Probably the most important change was that we were developing the same allogeneic CAR T-cell in the oncology space, and we chose to focus only on the autoimmune space rather than both. And I think there are several reasons for that. One, I grew up in some regards in the autologous CAR T-cell space, and it's very clear I understand they're very difficult to manufacture. Most patients in the United States and around the world who have diseases that would benefit from them will die without ever seeing a CAR T-cell. But the real rate limiter has moved from the manufacturer to the provider, right? And so there just isn't the capacity in the system right now to treat many of these patients. And so particularly at the academic centers that run these clinical studies.
And so we were increasingly enrolling the studies really almost exclusively outside the United States. And so then when you take that and you look at what's the regulatory path likely to be, right? It's most likely going to be some type of a randomized head-to-head study. And I think it's great if we would have run it. It probably would be a very good investment. We just didn't have the capital to do a multi-year, multi-hundred-million-dollar head-to-head study against some type of standard of care. And so we chose to focus on that.
How much might that apply to autoimmune then, some of those points on patient recruitment?
I think that it does apply. In terms of the challenge of enrolling, to be very clear, there are multiple challenges to enrolling patients in the autoimmune setting. One is, since you have this kind of curative intent, the number of people who have some type of a B-cell targeted drug, I think, as most people recognize, they crawl out of the woodworks like ants or roaches, right? I mean, we're everywhere, right? There are so many different modalities and targets. That's great for patients, but it's made it more challenging for drug development. The second is in almost all of these cell-based therapies or bispecific antibodies, there is a real desire to have experienced physicians on the ready, right, to treat things like cytokine release syndrome with the neurotoxicity from T-cell activation.
And that capacity generally sits in the oncologist, not with the rheumatologist where we refer them. So you have to kind of get them to work together, and then there are not excess capacity beds right now in the oncology setting. So I do think it's a real challenge for the field in moving quickly in the autoimmune space is just the paucity of places to treat these patients.
I see.
Particularly in the United States. It definitely is something that will impact us in both places.
Okay. So you're acknowledging the challenge. Okay, got it. Okay. It's a target you'll pursue, but it's a challenge that will have to be addressed.
Yeah. It's just worth doing there, I think, because it is competitive, and there are a number of different modalities. I think it's almost certain allogeneic CAR T-cells will play a very important role in treating autoimmune disorders. My guess is that more than one approach will work within the allogeneic space. It's scalable. It's off the shelf and ready for patients, and you can treat with curative intent. And I think it will be relatively safe, but you're going to have some of these challenges.
Got it.
It's a little bit of a land grab.
I have to move quickly, and maybe just in passing, because I want to come back to the pancreatic islets, but your CD22 program, are you also of the opinion that CD22 as a target has less neurotoxicity than CD19 as a target?
CD22 is a target because you're going to treat patients who have failed a CD19 CAR T-cell and they only have a few months left to live. The patients are easy to identify. There's very little competition for them. There is a lot of desire to get them treated pretty quickly, and the regulatory path is very simple, right? You just need to show that your drug works. I don't think you have to go forward. Now, there's another challenge.
You could pursue cancer then.
What's that?
So you could pursue cancer with this.
We are pursuing cancer there.
Okay.
We are pursuing cancer there. And you could get that too. I would be very surprised if it didn't work in the autoimmune space. I presume CD19, CD20, CD22, they all target pretty similar stages in the B-cell, will all have some benefit for patients. They may be slightly different in the people that they help. And it's worth exploring at some point, but that's the.
But is there a tolerability difference versus CD19 CAR T, in your opinion?
What's that?
Will there be a tolerability difference versus CD19 CAR Ts?
I would be very surprised.
The neurotoxide?
I mean, so the only part that might be a little better, so if you look at the B-cells that are hit by CD19 and CD20 or, say, BCMA, CD38, they hit plasma cells and some B-cells. The problem with that is the plasma cells give us our long-lived immunity, and almost every patient has gotten these events, a long-term IVIG. That's the problem in this space. CD19 hits plasmablasts and B-cells, and when the drug goes away, generally the B-cells come back, right, and the patient's immune system comes back. My guess is, so CD20 and CD22 are more or less the same expression as the CD19 and B-cell lineage, but they're not in some of the earlier cells. That may be a theoretical safety advantage.
It's not as deep.
Yeah. It may be a theoretical safety advantage in that you may have a slightly lower risk of infection. It may be an efficacy disadvantage. I think it will need to be teased out clinically. I don't think it's an easy one.
Got it. Okay. Excellent. So back to pancreatic islets. I guess I always get this confusion. I always ask you the same question. Hypoimmune technology, is that what improves the survival of the cells? Is that where?
Yeah.
So less immune reaction in the cell?
It is. So the real challenge in all of cell-based medicines to date has been basically trying to make cells that can engraft, function and persist broadly, right, that you can scale. And the problem has been with autologous cells; they are difficult to scale, and allogeneic, we will reject them. We put my cells into you; you will kill them. And so what the field has known is that there are two big arms of the immune system. There's the adaptive immune system of B- and T-cells. It's actually relatively easy to deal with that. You knock out expression of MHC class I and class II. The problem with that is that tumors, cancers figured that out a long time ago.
And so we developed something called parts of the innate immune system like natural killer cells that will kill every cell that doesn't have class I and class II on it. And so the challenging aspect has been trying to figure out how to turn off that natural killer cell. So it's kind of our unique capability, we think, is that we've figured out how to turn off both the adaptive and the innate immune system through a series of gene modifications. It's really just three. And I can confidently tell you we have solved the problem of allogeneic immune rejection in a non-human primate. I can confidently tell you we've done that in a mouse. We've done it in a humanized mouse. Everything we've seen in humans is consistent with that going into human.
I think the killer experiment is this one patient with type 1 diabetes, and if that works, you can confidently say we've solved it in humans as well.
Got it, so where are we with the trial?
We'll have data soon. So.
You're dosing?
We haven't said that. One patient should be determinative of whether it works or won't.
Oh, so the first patient's in the process of getting recruited.
If it engrafts, either a patient will reject it or they won't. And I've asked probably 100 different immunologists how you come up with a false positive if it works, and no one can come up with it. If it works, it's going to be generalizable. There are two reasons the drug may not survive. One is when you transplant cells, sometimes they just don't engraft. That means you just got to do it again. That's not an immunology problem.
Right.
or we may have an Achilles heel that we find, and we have to go and really go out. There's immunologic rejection of these cells, and if that's the case, then we've got to kind of redo things.
If there's an immunologic problem. Got it. Got it. Manufacturing scalability, is that a question mark or not really?
So what we're trying to do is gene modify stem cells, grow them into islets, and transplant them. And there are four main challenges to do that. The first one is making a gene modified master cell bank with genomic stability. So every time our cell divides, you kind of make one or two mistakes. No big deal generally. But inside our bodies, because we have trillions of cells, you have every single gene mutated. But generally, we've got a system that's set up to control that, right? When we're manufacturing these cells, we're putting them in a growth media that selects for cells that grow quickly, right? So you end up with problematic mutations over time, like DNA repair enzymes and things. So we don't want that, right? And so we've had to figure out how do you hold on to a stable genome and pluripotency. That's part one.
I think we got that. Part two, you need to make cells at a purity, potency, and yield for a phase one study. We got that, I think, right? I wouldn't worry too much about it. Part three, you need to overcome allogeneic and autoimmune rejection of these cells, right? Because you have a pre-existing immune response in type 1 diabetes to the Beta cell. Again, that's what this experiment that we'll have for you soon will tell you. So then we got three of the four major challenges done, and you should feel pretty good about our ability to run a phase I study. Question four, making this consistently at a purity, potency, and yield to be really commercially important. That's hard. That's really, really hard. And you've yet to see a stem cell-derived cell-based therapy at a commercial scale, right? It does not exist in the industry yet.
I think it will be a gradual process for us to get there, and I don't want you to walk away thinking we've solved that.
Right.
I think it's not a capital problem. It's not a scale problem.
It's a time warning.
Right now, it's a science problem.
I see.
I think we have to solve some of the science of that.
Got it. Excellent. So is it reasonable to assume perhaps around JP Morgan timeframe, we could hear back on the first patient and engraftment, or is that too early?
We've said late 2024 or 2025.
Okay.
So it's possible. I wouldn't say it's going to happen. It's possible.
You got to call me on that day.
What's that?
Call me that day.
Yeah. It will be like one of the more interesting results I've seen in a long time.
No, no. You've talked about it for a while.
Yeah, we've talked about it for a while, and I feel like it's Godot. We're waiting for it. I hope it isn't like Godot. I hope Godot actually shows up this time.
Outstanding.
Yeah.
Good luck. Thank you, guys. Thank you very much.