Welcome back to the forty-fourth Annual TD Cowen Healthcare Conference. Marc Frahm from the biotech team. So thanks everyone for sticking around for what I believe is the last session of the corporate presentations, although we do still have some physician panels to keep everyone interested for the rest of the day. But we're really happy to have, for this last session, that, you know, we saved the best for last. Hopefully, Steve. No pressure.
I was gonna say-
No pressure. No pressure, no pressure. We have from Sana CEO Steve Harr. So maybe Steve, for people who either are, haven't been following Sana much or maybe have lost touch over as you've kind of worked towards the clinic, you want to just give a kind of an overview of the status update and kind of the key events that you see over the next 12 months or so for the company, and then we'll get into specific questions about programs.
Thank you for having us, Marc, and thank you, everybody, for joining us, and I'm sure you guys recognize we'll make forward-looking statements as well. So we just filed our 10-K, so feel free to peruse the risk factors; it's pretty thorough. And so you know, the company was founded really around two platforms. And we're really trying to solve the challenges of cell and gene therapy. One relates to trying to hide allogeneic cells from immune recognition, and the goal there would be to be able to really make cells, allogeneic cells and transplant them and, you know, kind of really move towards scale. The other was for in vivo delivery, and we'll park that for a second and come back to it.
I mean, we really focused the company last year a lot around, for now, around this hypoimmune platform we call it, which is hiding allogeneic cells from immune recognition. And we now have four drugs in human testing across three different therapeutic areas, all of which should have, you know, some form of data this year to help us understand exactly where we are on the journey. The three areas are Type 1 diabetes, B-cell-mediated autoimmune disorders, and blood cancers, right? And so I'm gonna go through each of them. The most advanced, and the one we've shared a little bit of data on, is a drug called SC291. It's in development for non-Hodgkin lymphoma and CLL. We'll have. We've been going through the dose finding. We put a little bit of data out earlier this year.
I'm sure we'll go through it in a bit more detail. It kind of smells like it should after a few patients, but there's a lot more to learn with that. And, you know, we'll have hopefully a good bit of data as we move at least towards the end of 2024. The second drug in that space is a drug called SC262. It targets CD22, and it's for people or patients who have failed CD19 therapies. The IND was cleared at the beginning of January. We'll be going through the dose escalation as we move through 2024. I think we'll have a decent idea if it's doing what it's supposed to do again as we get towards the end of the year.
In the B-cell mediated autoimmune disorders, I think many people, including us, have been really thrilled to see the data in particular that's come out of Germany, and it's beginning to be replicated by others in treating diseases like lupus nephritis, extrarenal lupus, and myositis. And we've known for a long time that depleting B cells can have a you know really nice effect. We've known that the more you deplete B cells, the better the patient does. And we know that you know the CAR T cells are probably the best B-cell depleters that humanity's made to date. And so it's great to see the data play out with that consistency.
And we'll know, I think, as we move through this year, if that our drug, which we've scaled and is an allogeneic cell and can, you know, be dosed hopefully for tens of thousands of patients, if it works, if it looks as good as the autologous cells. I mean, that really is our goal, and it's not more complicated than that. 'Cause I think if we can do that, we can really have an important medicine. And then the fourth area where we'll have data is in type 1 diabetes, and, you know, I think you most people recognize type 1 diabetes as a disease where the immune system kills the patient's beta cells. And it's treated now with insulin, it works pretty well. But if you're a patient, I think many people would say that that's just not a great solution.
But our goal here is to be able to treat patients with single therapy and have them euglycemic for life, with no insulin and no immunosuppression. And we kind of already know that you can replace islets or beta cells, and that patients, in the context of immunosuppression, can get normal blood sugars. So really the first question out of the gate that we're asking this year is: Can we eliminate the immunosuppression and see function of these cells? And again, that's a study that should read out relatively soon and pretty straightforward. So you know, what we're really trying to do is go after a lot of diseases that actually people get, right? So they're not, these are not orphan diseases.
These are relatively common, disorders with products that we can scale from a manufacturing perspective and deliver to patients at, hopefully, a cost that the system can afford. We'll learn a lot this year.
Maybe just sticking on the allogeneic cell therapies, just kind of what are the limitations and challenges you've seen? You know, there are a number of programs that have gone into the clinic kind of ahead of you with different approach, a range of different approaches.
Mm-hmm.
Just what has the field learned from those and, you know, how is that being applied to 291 and the other-
Yeah
Platforms?
I would say the field's learned that basic, what's happened in humans is completely predictable from biology, right? I mean, I think that every one of these has been very predictable. And what you know, there are basically two important when you put my cells into you, your immune system will kill them, right? It's been known for a long time. And there are two important arms to the immune system that we have to grapple with. One is B and T cells, right? And that's been relatively easy to deal with for years, and the way you deal with that is knocking out MHC class I and MHC class II. The challenge is that viruses and cancer figured that out millennia ago, and we evolved natural killer cells to kill cells that don't have MHC class I and MHC class II.
So the real challenge, the real challenge has been trying to turn off the natural killer cells or the innate immune system, once you've knocked out the adaptive immune system, B and T cells. And what you've seen over and over again is, if you haven't grappled with that challenge, the cells are rapidly rejected. And in fact, in CAR T cells, when you lymphodeplete a patient, the first cell back is a natural killer cell. So if you've done nothing, the patient probably has a bigger therapeutic effect than they would if you knock out class one and class two. So that's what we've seen happen in humans, and it's, you know, it's consistent with the preclinical data.
We're optimistic that what we have shown. I think we've shown that we can get rid of allogeneic rejection in non-human primates, in mice, in humanized mice. And the real question is: How do those data translate into people? You know, we can come back to why we think what we're seeing in humans in the early settings is highly encouraging. But that really is the question. I mean, 'cause the data have been translated into people. Like, it's not nothing's been that surprising.
Yeah, maybe touch on the mechanism that you're using to get around NK cells, and could-
Yeah.
How well-defined is that system, right, with CD47?
Yeah. So, what we do is very simple. We make three gene modifications. We knock out two different genes that deplete class I and class II MHC. So now you no longer have a T cell or B cell response. And then we overexpress CD47, and the real insight, and it was not what we expected, right? So the way that the team went about looking for this was kind of the paradox of pregnancy, right? So, you know, we're all half mom and half dad, but we're here because our mothers didn't reject us in utero. And really looking at what was unique about that maternal fetal border, and then trying to eliminate it down to the base number of, to the minimum number of changes you need to make.
The real discovery is that natural killer cells in humans, if you just look across our repertoire, all of them overexpress the cognate receptor for CD47, SIRPα. So if you overexpress CD47, you turn off natural... It was always thought as a 'don't eat me' signal, right? Which is things to turn off macrophages. And it was learned that it would, you know, is a much broader impact. And so that's been the insight. You know, it seems to be working across multiple species, including humans, and, we're optimistic that by turning off natural killer cells, macrophages, B cells, and T cells, that nothing else is... The risk could be some other thing rears its head that we haven't thought about.
And-
Right, I mean...
You know, so that pathway has been drugged, attempted to be drugged, right? The CD47-
Yeah.
To take, yeah, with antibodies and, you know, and things like that. Magrolimab, you know, with, you know, maybe some early signals that looked promising, but then magrolimab obviously in phase III-
Yeah
Has now failed. What is— are there any learnings from that, those attempts that are useful for kind of looking at SC291?
Nothing. The only thing that I would say that's important about that is we've shown across multiple studies, including a recently published non-human primate study in Cell, that if we infuse with a CD47 antibody, our cells will be eliminated. It's a beautiful safety switch, right? And so I would really like one of these companies to get their drug approved. It would make our life a lot easier because you have a then-marketed safety switch that a physician and patient could use if something, you know, unexpected, untoward happened. But the mechanism that's utilized to kill a cancer cell, for example, with a CD47 antibody, has really nothing to do with our mechanism. I can get into why, but it's really that. There you have a cancer cell with CD47 on it.
The hope is that you will induce antibody-dependent drug killing, N K cells will come and bind the antibody itself and begin to kill. That's not what we're trying to do.
Okay, and then on, just thinking through persistence, right? That's what you're kind of trying to-
Yeah
Solve for, right? Is the cell staying around. What latest thoughts on what's the necessary amount of persistence, and how does that vary by indication, right? I mean, just for CD19, you've got various oncology indications-
Yeah
Autoimmunity.
So, I mean, I'll go through just simply. If it's in for the Type 1 diabetes drug, it's for life, right? I mean, that's kinda what we're looking for. With the CD19 CAR T cell, you're absolutely right. It is indication specific. And I think if you look at what the current clinical practice in something like acute leukemia is, that if a patient's cells are gone before six months, they will transplant the patient, right? So you need them at least six months. I think if you look at the autologous CAR T data in non-Hodgkin lymphoma, it's probably somewhere between three and six months. I think if you look at CLL, we don't know. There just isn't enough information. And autoimmune is very different, or maybe very different.
I don't think any of us really know exactly, well, if, if long persistence is a feature or a bug, and I think that's an unanswered question. There's kind of a set, so the goal of these CAR T cells in a disease like lupus or multiple sclerosis or myositis, it seems to be to get rid of the pathogenic B cell, right? So it's almost like a Control, Alt, Delete for your antibody immune system-based immune system. And so anything that has to surveil your whole body is gonna take more than 24 hours, right? But it probably isn't a year, 6 months or a year, right? And I don't think any of us know the answer yet. I think from our perspective, the data that have been shown with autologous CAR T cells are really quite impressive, right?
I mean, basically, 100% of these patients are in remission, in a drug-free remission, and you're now getting multiple years, and you're seeing portions of their immune system, like their ability to, you know, look for the vaccination responses and things, reconstitute. So we're just very simple, just look like the autologous cells. And because we have, you know, those autologous cells are made from a patient's own T cells, and that's very complicated for the physician and patients even just to make and to administer, and very difficult to scale. So if we get this right, and we look like those, we think we'll have a really important drug.
Okay. You mentioned on CD19 in oncology, you have released a bit of clinical data.
Yeah.
What has been learned so far about that? About that part. What do you think are the major learnings from that data set?
So far. So what we've disclosed is we had, you know, early data. Six patients treated, four evaluable at the time. Two of the first four—we were in a dose escalation, so it's a low dose, beginning to get in the right dose, probably, you know, the right dose or a little high, right? Just based on our approved drugs. So what we saw is two of the first four patients are in a complete, ongoing complete response. One had a partial response, and one had stable disease. So it smells like it should, right? There were no drug-related side effects, no things like the cytokine release syndrome or neurotoxicity that's been seen to date.
What we showed was there was no evidence. The way these allogeneic CAR T cells are made, we take, like, your cells and send them to a plant, we gene edit them, grow them into enough cells for hundreds and hundreds of patients, and then release them. And when you do that, we make 5 gene modifications. And so some cells have all of the gene modifications, and some cells have only some of them. And so what should happen in a CAR T cell is that if you have an intact immune system, you should generate an immune response to your unedited cells. And your fully edited cells, the immune, your immune system shouldn't see. So what we showed you was that's exactly what happened, right?
So, patients who've been dosed in the study have generated T cell response that kills the unedited cells. Their NK cells will kill cells that don't overexpress CD47. They generate an antibody response, generally. We'll come back to that in a second. Some of them will generate antibody response to unedited cells. And the edited cells are completely blind, right? The immune system just doesn't see them. Right? So that's what we've shown you. There's no immune response as we look out over time to our edited cells. We haven't gotten into how long the cells last and things like that, but we'll put that into some kind of scientific presentation. But they kinda smell like that.
The two patients that are in PR and stable disease, are the cancers depleted? Are they losing antigens such that-
Are they what?
So, are the cancer cells losing antigens such that the CAR Ts are no longer finding them?
Oh, the two patients that don't have a complete response?
Yeah.
I don't think we know much about them yet, right? I mean, it's an early phase I study. So the question was: What was the mechanism for resistance for the patients who didn't respond? We don't know. I mean, one's a CLL patient. CLL has, you know, the Bristol study was an 18% CR rate, so you couldn't expect it to be a very high level to begin with. We'll learn more as we go forward. I don't know if it's a patient problem, a drug problem, or something else or-
Target trying to swap out your mic.
Mine's not really working? No, you good.
Thanks.
Welcome. Okay, so you were starting to say the... you know, so you've kind of done this immune analysis. You, one piece of data you'd like to get out eventually is the direct measure of persistence, right? Which would be presumably like a PCR for the CAR construct. Is that the right way to think about it?
Is it the what?
A PCR for the CAR construct?
Well, so, kind of, right? That would tell you the cells are around. One of the things that we've kinda tried to focus people on is, because we have fully edited and unedited cells, right? What you would really like to see to know you have an intact immune system is that all of the unedited cells are gone, and the cells that are fully edited still are around, right? 'Cause then you have cell survival in the context of an intact immune system. So to do that, you need to actually find the cells, not just do PCR, right? But PCR can tell you, hey, there's cell survival. That's a great marker. The ultimate, most stringent test will be: Do you have cells? Do you have the cells that survive all having fully edited, you know, the fully edited profile?
You need to do, like, flow cytometry or biopsies and things. So it's a more rigorous test.
Okay. And then, you know, I think you're also guiding to a clinical update, not just, you know, these translational types of pieces. So how should we think about that next clinical update?
Yeah. I think most of you guys have told us that you really wanna see six-month complete response, right, right? And that's. So to go back, you know, autologous CAR T cells in the lymphoma setting have been you know, really, you know, quite impressive, and it's very rare that you will find a patient recur or relapse after six months. In fact, they're basically case studies, right, in lymphoma. And so if you have a complete response at six months, it really seems to be good, and if it's less than three months, there's a reasonable chance the patient's cancer can still come back, and three to six is kind of very gray.
So I think the next important clinical update from us is enough patients with six-month complete response rates for all of us to begin to get a sense of how we're gonna compare to these autologous CAR T cells, which are quite good. So that's the kind of thing that, you know, will take us towards the end of the year to get. I just kinda think ASH is a reasonable time. We may give you some other data in the interim, some mid- of the year thing like ASCO or EHA, but my guess is that the real meat will be on the bone by the end of the year.
And how definitive do you view that six-month type of durable CR? You know, I think one of the key pushbacks the broader team here at TD Cowen has heard on Allogene's data is that there's a view among some investors that there are some relapses later than six months. And what does that mean for allogeneic approaches? And is that-
Uh-huh.
Is that really translatable, that kind of hard bar that-
So if you look at the durable complete response data from Yescarta, supplement to ZUMA-1, right? You can just look it up. 96% of all but one had—were patients that had a durable complete response, had persistent CAR T cells. Sorry, that's not true. 96% of people, 96% of people who had a complete response and persistent CAR T cells had a durable complete response. Basically, one patient who didn't. So that's really clear. 91% of people who had a complete response and persistent CAR T cells at three months had a durable complete response. So there is something about that ongoing surveillance that's important. So we just, you know, we need to—we, you have to put the whole picture together.
My guess is that a lot—the allogeneic approaches to date are really simple. They beat up the immune system. As soon as the immune system comes back, the CAR T cells go away, right? I mean, that's 100% of what's happened. And so all the patients' immune systems ultimately recover. And so what we need to see is that we have cell survival in the context of an adaptive immune system, 'cause then you've got something that smells like an autologous CAR T cell.
You know, in order kind of just to make the math work, that you, you know, because, of course, unfortunately, the majority of patients don't even get a CR in large cell lymphoma, let alone a durable one out at six, nine, 12 months. And to make the math work that you have, you know, not just an anecdote of a person at six months but, you know, reasonable proof that there's real six-month durability here, it seems like you're gonna need a fair number of patients at the top end of that funnel into the trial. Is that fair?
Mm-hmm. Yep.
And-
It's not gonna be 100%, right? So you, you've already seen it's not 100%.
Yeah.
Yeah, you need a decent number of patients by the end of the year to kind of begin to understand it.
How are you enrolling kind of across indications there? And how should we think about... Right, 'cause there's a variety of B-cell. You know, you already touched on CLL. The response rate is much, much lower than DLBCL. I mean, is this trial starting to focus a bit more on DLBCL in terms of enrollment?
No, if you look at CLL, if you look at the... Again, I think CLL, be very careful how you look at the data. MRD, minimal residual disease negative, like that's about—it's over half of patients, and it's a very strong predictor of long-term, durable, complete, durable remission, right, and survival. Not 100%. 100% of patients with CR are in a disease re-state still. It's pretty incredible data, but your point is well taken, which is that just CRs aren't as common. So you wanna look at MRD to really understand how well the drug's doing. We will, in phase I, the most important thing for us is to establish a dose. We need to get through the dose escalation and establish a dose. So that's really what we're focused on.
You know, it's unlikely that the dose, you've seen the evidence, will be different across different indications. So really, we wanna include in here different indications so that we can confirm that and get a number of patients of experience. Phase IB will really be about confirming the effect in individual indications, and that will then set the registration strategy, right? And so expect that you'll have data across large B-cell lymphoma, a host of indolent lymphomas, as well as CLL moving through this phase.
Okay, and then maybe quickly on autoimmunity, just can you frame up the size, scope of that update that we're likely to see at the end of the year?
Yeah
In terms of, you know, patient numbers- and things like that?
Yeah, so autoimmune, I think... Let me just kind of also just serve up why we're, what, some of the reasons we're so optimistic, right? I mean, one is the data are just really quite intriguing, and the opportunity is quite large. Two is if you look at the oncology data, I told you is that patients with an intact immune system should generate an immune response to our unedited cells. That's true for T cells; it's true for natural killer cells. What we see is that in the patients who got a complete response, they did not generate antibodies, even to the unedited cells, which is indicative of complete aplasia of B cells in that patient, right? And that is kind of Control-Alt-Delete, right?
And so, you know, again, that's not every patient in our dose escalation study, but that is a reason to be optimistic that we can have a really nice drug effect. The starting dose in these patients is higher than where we started in oncology. The effective dose in the autologous CAR T cells is lower, right? And so we start at 60 million cells in cancer, as an example, yes, CAR T is 2 million cells per kilo, call that 150 million-200 million cells in the United States. The dose in our starting dose in autoimmune, because we have this oncology data, is 90 million cells. The dose from the German group, as well as from some other companies, is 1 million cells per kilo. So call that, again, 75 million-100 million cells.
Hopefully, we're right in the sweet spot of where we can see efficacy, because, you know, in a dose escalation study, as you start each dose, you have to, in a CAR T study, you have to wait between patients, right? And so the number. The reason I bring all that background is the number of patients we have at the end of the year will be dependent upon whether or not that first dose is the right dose, or if we want to look at a second dose and kind of keep going. If you assume that first dose is right, you know, one would assume we have, by the end of the year, some number that's, you know, consistent with what you saw from the German group at, at ASH, something like that, maybe, you know, high single digits, low double digits.
If it's not, we'll have a, you know, we'll get through a couple of doses, right? So they're one a month. Just gotta take your time. So we'll just be, you know, somewhere in that range. And one can see here, though, the really rapid effect that is seen in these patients, right? They have, you know, complete responses within three months. And I actually think we'll probably have a pretty good handle if the first dose is right, if this is working or not, by, you know, sometime this summer, right? And I don't know what we'll talk about, but we'll present data before the end of the year.
And just broadly speaking, in oncology people are not really willing to sacrifice very much efficacy for convenience, and, I mean, if completely inaccessible, maybe, but certainly not if you can access. But in autoimmunity, we definitely do see therapies used that are less, clearly less effective than other options that are approved. Is there space? Do you need to match the autologous, in your view, here, or is there space for just a not quite as good therapy?
Yeah. I'd be careful with your first assumption. I mean, not that we don't want to look like, but, but bispecific antibodies do not have the, the long-term efficacy of a CAR T cell, but they're very difficult still for people, a lot of people to get their hands on. And bispecific antibodies do very well in oncology and are often used in front of CAR T cells, particularly in certain environments. All that being said, I think you're right, in autoimmune, it's much more complicated to give a autologous cell in the autoimmune setting. The beautiful part about them is, to date, the data look exquisite, right? The challenge is that even just to get this going, right? So you wanna treat a patient, you gotta find an apheresis slot.
You then have to taper the patient off of their immunosuppressant, hope they don't—their disease doesn't flare, take their white blood cells, ship them to the factory, restart the immunosuppression, make the drug, wait for it to get released, taper them off their immunosuppression, lympho-deplete them, and treat them. Right? That's actually a lot of work for a clinical site. It's a lot of work for a physician in the community over time. And that assumes that it's readily scalable, all these slots and drugs available. And these are very large diseases. And to your point, in the autoimmune setting, you see patients cycle through drugs over time. So, we could be a very—you know, you could have a very important therapy that is not as good. It would not be our goal at all. I mean, our goal is to be as good.
What's beautiful is, if that 90 million cell dose is right, you know, we're probably making, I'll just say, a number around 700 doses right now per manufacturing run. Put that into context. If you have an autologous cell, having done this before, where you do a 100 manufacturing runs, your best-case scenario is you treat 100 patients. If we do a 100 manufacturing runs, we can treat 70,000 patients. And the drug is available off the shelf tomorrow for the patient, instead of going through all of that tapering and coming back. So we're optimistic if this works, we can have a really important medicine that's very broadly utilized. I'll be pretty surprised if we don't deplete B cells, right?
Is it possible we don't work as well, or we work better as-- than autologous cells? I think both those things are still on the table. We don't know the answer.
Okay. Then maybe in the last minutes here, Type 1 diabetes, where you have an open IST now working with a cadaver version of-
Yeah
What you would, you would ultimately hope to commercialize. What, what's success in this trial look like?
Yeah, this is the cleanest, simplest way to see, is this like truly driving immune evasion, right? Because the patient will not only have allogeneic response, they have a preexisting immune response to the cell we're transplanting, right? Because they have an autoimmune response against this drug. So we're gonna put this into a patient with no immunosuppression. So success, if you do that, you should see the cells die within a few days, right? I mean, this is really simple. This experiment is done all the time, right? It used to be done now, but now people come off immunosuppressive, they can't tolerate, they're gone within a few days. So what success here looks like is cell survival, right? In the context of no immunosuppression. And there are a couple of ways to show cell survival.
The lowest is to see cells that have been in the arm, and you can image them, and there's no immune response against our product. That's good. That'll be really good. You might still be asking me, are you sure those are those beta cells or it's something else? And so what we'd really like to see is C-peptide. So because the way that a beta cell makes insulin is you make something called proinsulin... but it's secreted as insulin and C-peptide. So if you have C-peptide, you have insulin production, right? And so none of these patients have C-peptide at all, detectable C-peptide at baseline. So if you see stable C-peptide expression over, let's call it a month, right? You know that patient is now making its own insulin and that we have evaded the immune system.
Now, you could get to the ultimate bar, which is that patients are off of insulin, right? I mean, think if you just decreased on some, we could be—that could, may, that just may have to do with patient's tolerance, and it'd take months for the hemoglobin A1c to go up, so ignore that. But if you have—if you're off insulin, that would be spectacular. I, I'll say two things: It probably won't happen, right? We're at too low of a dose to start. I'll be shocked if it does, so. But the second is, there's no difference in the value of the company. We know cadaveric islet cells at the right dose can get people off of insulin. The real question is, can you evade the immune system? I'm pretty sure there'll be a difference in valuation if that happens, but that's short term.
But the value of the company will be driven by, do you see, do you have true immune evasion and function in the context of no immunosuppression?
And unfortunately, you know, when you're using cadaver cells, sometimes there's just bad cadaver cells-
Yeah
That has nothing to do with the immune protection that you're trying to engineer in. How do you differentiate that when you infuse this into, when you inject this into patients and you end up a few weeks later, there's no C-peptide? How do you know if that's because the cells were bad versus-
So to start with, you can just look. We have product, and you can just see, is there immune response against our product, right? You just go back and run the assays. So if there's immune response to the product, we got problems, right? If there's not, we should do this again, right? And just do it again. Ultimately, what we will do if we need to, is we will transplant these cells in the context of immunosuppression, see engraftment, and then withdraw it. I mean, that's a pure test. The thing is, immunosuppression is, you know, this is the first time you're putting a gene-modified cell like this into a person. The physicians really felt like they didn't want to also throw on top of that unnecessary immunosuppression if you didn't need to.
So we'll run that experiment if we have to.
Okay. Unfortunately, we're over time, so we're gonna have to cut it off there. But, thanks a lot for joining us.
Thank you.
And everyone-
Appreciate it, Marc, and thank you, everybody.