Good afternoon, everybody. Thanks for joining us for the next session here today. Very pleased to have Sana with us for the session. Quickly before we get started, I need to read a disclosure statement. Please note that all important disclosures, including personal holdings disclosures and Morgan Stanley disclosures appear on the Morgan Stanley public website atmorganstanley.com/researchdisclosures.
And from Asana, we have Steve Harr, the CEO joining with us. Steve, I'm going to turn it over to you to make some opening comments and then we'll go right into Q and A.
Great. Thank you, Matthew. And since you made your disclosures, I'll do mine quickly, which is we'll probably be making forward looking statements. And we and our lawyers spend a bunch of time on the risk factors in the queue. So take a look at those before you make any decisions.
It can be very helpful in understanding our risks. So SADA was a company founded on the belief that 1 of, if not the most important transformation that will occur in medicine over coming decades is the ability to modify genes and use cells as medicines. It's what we call engineered cells. And our goal is to build 1 of the leading companies of that era. And to make to kind of like go straight to the point, when you are 1 of the most important decisions that the company made when it was getting going was a lot of people want to pigeonhole us into being a gene therapy company or a cell therapy company.
We really looked at those as the same thing, right? And so we are an engineered cell company. We do it sometimes inside the body and sometimes out. What that's allowed us to do is build capabilities at a scale that we wouldn't be able to otherwise. It's allowed us to attract better people because the best people want to work where they can have the biggest impact.
And it's left us with a portfolio where we actually have very different risks. 1 of the great things is the capabilities are relatively similar, but our risk profiles are quite different when we go in vivo or ex vivo. So the way we approached the in vivo gene modifications was a really simple idea and that is it in order to modify the genome you have to deliver a payload and that payload then has to do something, right. And it turns out that you can do most things you want to, to the genome in a Petri dish and the real challenge has been in vivo delivery. So we focused on the outset on delivery with the goal of being able to deliver any payload, DNA, RNA, nuclease, protein, whatever, to any cell in a specific and repeatable way.
And every time we do 1 of those 4 things, we kind of create a whole new category of medicines. And we started with technology that allows us to do cell specific delivery, so for example, just to a CD8 T cell. And we can really deliver any type of payload, right, DNA, RNA, protein. And we've then spent a lot of time and effort on our gene modifications, genetic capabilities as well. So that's 1 platform.
On the ex vivo side, you want to be able to manufacture cells at scale that will engraft function and persist. That's how you make medicines. And the fields made really good progress in doing all of that with autologous cells that they're really hard to do at scale. And then with allogeneic cells, it's very hard to get them to persist or hide from the immune system. And we really we made the choice to really start the company around some technologies that allowed us to hide cells from the immune system.
And we've made really great progress. We can now show in non human primates, we can transplant allogeneic cells with no immunosuppression. They live out months months, right? And so those are the kind of the platforms around which we found the company. We're moving forward with a pretty broad pipeline.
There are probably about a dozen drugs in latter stage preclinical development for candidates, we should call them. And not all of them will make it. Our goal is to build a pipeline that allows us 2 to 4 INDs per year. We'll start as early as next year. And what comes out of the gate will be really focused on T cells.
There's an allogeneic T cell platform utilizing this cell cloaking or hypoimmune and then there is an in vivo CAR T cell generation, which is really from this ability to deliver payloads directly to cells in vivo. And we'll expand beyond that. They can get into that as we go. But that's just a little bit of the background. We certainly aren't a T cell company.
T cells are important part of what we do and it's going to be the first parts that go into humans and likely tell us we have more work to do where we're making real progress with these platforms. And we are then behind that areas where we leverage them going after a host of different diseases.
Great. Good. Thank you for that interest, Steve. So maybe we could take each of the 2 platforms sort of in hand and just walk through them. So maybe we could start with Fusogens and just give people some background because I'm sure not everybody is familiar with them even though there are a lot of Fusogens out there.
So what's a Fusigen? How are you using it? And then why did you pick sort of in vivo cars as the first way to go about sort of demonstrating their utility?
Yes. So, first 1 of my lessons has been if you're faced with a complex biologic problem, see if mother nature has already solved it and if she has leveraged that system. And viruses are able to deliver genetic payloads in vivo in very specific ways to different cell types. For example, HIV only goes into your CD4 T cells. And the COVID only goes into cells that have the ACE2 receptor on it.
And you then then we have really leveraged this system in mammals, for example, human sperm only goes to human egg. It doesn't deliver a specific payload to any of the cells that it goes by on the way. And we really took that system and we're leveraging it in a cell specific way. So what we did is we took a viral Fusigen. We neutered it so it no longer recognized anything.
We then put on it a binding moiety, so it will find the cell that we're interested in. It's called CD8 for CD8 T cell. And then we do a lot of protein engineering to build back up the potency of that ability to kind of like spear into and deliver genetic payload into the cell target. So that's basically how we build them. We then put them we have to put that Fusigen onto some lipid bilayer.
It could be a cell, which we do, and it could also be on a viral like particle virus like particle. And so what we started with was taking a modified lentivirus. So remember lenti is a modified HIV. And we took the fuzing on lentivirus is something called DSVG that targets the LDL receptor, which means it gets into basically put in different packaging, so we don't have to use put in different packaging, so we don't have to use all the random integration of lenti or we can choose to use it, it's our choice. So that's what we started with.
And the reason we went after T cells first was, 1, it just happened to be 1 of the first places we got this to work. And we can kind of get it to work in almost any cell type you ask us to, but we got it to work with really high efficiency. The second is that we're using a payload, essentially a carrier that has a pretty limited volume of distribution, right? It doesn't go everywhere in your body. And that is beautiful from a safety perspective we're going after things that exist in the blood, bone marrow, spleen and liver.
And it's challenging if you want to go in the brain, right, so it's a direct. But it's really nice from a safety perspective for us to go after T cells or HSCs just because they can get there pretty easily. It doesn't go a lot of other places. So that was it was kind of practical and biologic that led us there. It's kind of where we got it working first.
And then maybe the third is, it's a really simple place for us to prove this works well enough or not, right. We know the model. We know let me give you an example. We went after Alzheimer's disease and we didn't have the right effect. We wouldn't know if we had the wrong biologic hypothesis or if our platform didn't work well enough.
By going after a CD9 creating a CD19 CAR T cell in vivo, it doesn't work really well Where the biology has already been proven. If we get it right, it will be a very meaningful medicine. I mean, is it just a marked improvement over the way things are done today? And if we have a challenge, we'll know it's because our platform isn't working and we need to modify it, not because we have the wrong biological hypothesis. CD19 CARs clearly kill cancer cells, right?
That was kind of why we chose that.
Okay, great. Good. And then maybe since you're obviously not in patients yet, talk about the derisking data that you do have, especially the derisking data in animal models to give you confidence that you have solved some of the problems that you talked about?
Yes. So, there are a couple of things that we've done. In vitro, we want to show as much as we can that we are specific and that we're highly efficient in getting into the right cells, right? So that's done. The second is to look at really in vivo, first of all, can we transduce a reasonable number of cells in models, which is true?
And then what is the biologic impact, right? So, 2 ways to test that. 1 is there is kind of the definitive mouse model that's been utilized for B cell malignancies across the board for CAR T cells. It's called the NALM6 mouse. And so there what we do is we compare a single intravenous injection of our medicine into the mouse with kind of a CAR T cell that's been made outside the body and delivered.
Our data is in the S-one or our presentation. You can see we get comparable efficacy. The second and I would say a more challenging 1 is to put this into a normal immune monkey and deliver a CD20 CAR. And just turns out you have to do CD20 because CD19 doesn't cross react between humans and monkeys. And see if we can deplete B cells, which is the target of CD19 or CD20, right?
And that gives us a real insight into in a normal immune animal, are we able to deliver with just a single intravenous infusion, enough medicine to make enough CAR T cells to have a clear biologic effect. And there in the majority of monkeys, the first time we did this at a single dose, we saw B cell really meaningful B cell depletion. And so that was to me that's kind of the killer experiment. So that leaves us running really towards 3 things to get our human testing going. 1 is scaling GMP manufacturing, always easier said than done, right?
The second is these animal models aren't really that, they're not the same as going into human cancer patient and doing our best to understand what should be our starting dose. The dose is really not clear. And the third is the normal is just pharm tox work. Where does this go? Does it go anywhere besides T cells?
And when it gets to whatever cells it goes to, does it integrate? And to be really clear, CD8 is on T cells and some NK cells. So we will get into NK cells, some NK cells as well. You say that's good. You can say that's not so good depending upon your belief of NK cells.
I happen to think it's good. But that's a little bit around kind of where we are. Okay.
Okay, good.
And our goal is to be in human testing, right, as if things go well, we'll be there. Hopefully, next year, we'll get that off we go. Yes.
And maybe now is a good time to touch on manufacturing, what you're doing there in terms of being ready and any sort of unique challenges that you faced in manufacturing here different from some of the other cell therapies?
Yes, it's very different. So this is think of this more like AAV or lentivirus than a cell therapy. It's a gene therapy in terms of manufacturing. And if you watch this AAV panel a couple of weeks ago at the FDA, I think 1 of the things you noted is, if you watch this, the FDA is kind of getting to understand that maybe there's we measure dose and there are capsids that have all the genetic material and there are some that don't, right. And this is a system that people have been working on for 20 years, right.
So you can imagine a system that we are getting going, we have to really understand kind of what percentage of ourselves are really well packaged and what happens in those that aren't. And then we have to scale that process in a kind of a proprietary way. And so, again, like any gene therapy, you're going directly into the body. So you want it as pure as possible, right? So this is 1 where manufacturing is a challenge.
And I feel good about where we are. We don't have every I dotted and T crossed, but feel good about where we are to go in and run our 1st in human studies. I think if you said where are you in terms of commercialization, we have work to do to be at the scale and I would say quality and predictability of what we want to have for when we would want to globally commercialize this. I don't think that that's unique. I mean antibodies have that.
But antibodies you know exactly the road you take to get there. We're more like the antibodies 15, 20 years ago where we're going to have to figure out some of that road as we progress going forward. So we have work to do for some of that.
Okay, perfect. And then before we move on to hypoimmune and sort of ex vivo concepts, maybe just talk about beyond T cells, how you're thinking about using fusigens?
How we're thinking about doing what?
How you're thinking about using fusigens beyond T cells?
Yes. So there's a lot to do in T cells, to be clear. And there are a couple of things that are true. 1, using the carrier we use today, as I mentioned, our volume of distribution is somewhat limited. It's a great thing.
The cell types that are most obvious for us to go after would be things in the liver, either hepatocytes or something like liver sinusoidal endothelial cells, something like that, but different cells in the liver and then hematopoietic stem cells, right. And we can get at both of them. We have a reasonable success. We now take that reasonable success and turn them into medicines, right. So if you look at those both for prioritization and complexity reasons as well as just for bandwidth and biology reasons by the way to say, Those are earliest or couple of years out, right, because we're really focused next year on bringing forward the T cells.
And so what I would say is we exit T cells, I think it becomes more and more important for us to think about what payload we put inside the cell and how we deliver it. And within T cells, we can rely upon millions of patients who have HIV and thousands of patients who have had CAR T cells to say that when you go to T cells you can integrate DNA safely and not lead to T cell malignancies. As you exit T cells and go into hematopoietic stem cells or hepatocytes or cell types, we don't have that same comfort, right? It doesn't mean they're not safe, but we don't have all that data. And it makes more sense to us than those to maybe go and deliver the gene editing payloads, whether that's simple things, call it CRISPR, TALENs or whatever or more complex things like base or prime editing or some other novel things that deliver bigger or different things than just knocking things out.
So stay tuned. Those are things that doing there. We're making real progress both in getting into the right cell and delivering new interesting payloads.
Okay, great. Good. Why don't we turn to hypoimmune then? And just like we did with Fusion and maybe explain the concept behind the hypo immune platform and what your sort of first target is there?
Yes. So really as the field of stem cells got going in the odds, 1 of the first things that the real leaders realized was that unless you could overcome the problem of allogeneic rejection, the field will be pretty limited in its impact and for human therapeutics. And you put my cells in you, you're going to reject them as foreign. And a couple of different places got the same advice and that was, this isn't that complicated. Really what you need to understand is the paradox of pregnancy and the paradox of pregnancy is that we're all half mom and half dad And the only reason we're on this call together is our mothers didn't reject us.
But really none or very few of us would be good organ transplant donors to our mother. And so really what's different about that maternal fetal border was the question. Really we came up with the teams came up with a really clear roadmap, I think. And the system that was built really seems to be working. And so what we've done now, we so the challenge and this is where the field has struggled is you have to grapple with 2 arms of the immune system.
There's the adaptive immune system of B and T cells and there's innate immune system of things like macrophages and natural killer cells. And the way that you deal with the adaptive immune system generally is you get rid of MHC Class I and Class II. That's been known for a long time. The challenge is that that's what viruses and cancers do to hide these cells in the immune system as well. And so we've evolved a natural killer cell to go after cells that miss this.
And really figuring out how to turn off both of those arms, the immune system at the same time has been something that people have struggled with. And as far as I can tell, we're the 1st group that's really kind of gotten this to work. And again, we have to get it to work in humans. Where we are is we've shown that we can inject allogeneic gene modified cells into monkeys. And with no immunosuppression, they will live for months months months.
We can do that de novo. We can also first inject non gene modified cells, which the monkey will create immune response to and reject and put ourselves in. So even when there is a pre existing immune response, our cells are hidden from the immune system. So it gives us like a lot of optimism that we can deliver allogeneic cells, whether that's T cells or stem cell derived islet cells or anything else, that we can do that and we can redose if we need to. And we can do that even if a patient has a pre existing immune response like in type 1 diabetes and multiple sclerosis and still hide these cells from the immune system.
And so where we are generally is in we've done really I think about as much monkey work as we need to get into human studies and we're really making GMP reagents and GMP therapeutics to move into human testing. Hopefully, we'll be get the IND in next year for the allergy program. That's where the odds are stacked in our favor. You're going to have you're creating you're putting an allogeneic T cell into a cancer patient who's immunosuppressed from cancer. They get a little conditioning chemotherapy because that's what you need to do to get any T cell autologous T cell or allogeneic T engraft.
We're going to go with CD19 and knock out their B cells. End of the day, we probably need these cells to last for a few quarters, right? That's the easy 1. The hard 1, which we'll do, hopefully, be IND in 2023, things go well, is type 1 diabetes is probably the first place. They can really go after really hard problems where you've got a pre existing immune response to the cell.
There's going to be no immunosuppression and you want this to last for years years years to be valuable. And those are a couple of programs that I'm really optimistic about. So that's sort of what we are.
No, that's perfect. And can you talk about cell lines, cells, like all the work, obviously you've got the technology to avoid the immune system, but then another piece is getting the right cell lines, getting the right cells and production there. So where are you in that regard as well?
So let me really we're applying this in 2 different camps, right. And so 1 is a donor derived allogeneic T cells. So it's a norm like it might be you or me just donating T cells. And there we have to do 3 things, right. We have to show that we can get very high efficiency in our gene modification.
We're doing 5 modifications, so it has to be very efficient.
The second is that we can
the second is we can create very high quality T cells out of that, right, at scale. And then the third is that we can control the donor to donor variability for 1 group of patients it's me and others for you that they get the same product, right? I feel we're really good on the first 2. The third 1, not that we've had a problem yet, but we're still in the process of proving to ourselves that we can do that, right? So that's where we are on that.
We then have the stem cell derived hypoimmune cells. And let's say that's a more complicated endeavor. First of all, we have to start with a GMP, it's called IPS cell bank with freedom to operate, right. And there's a lot in there. And once you have all of that, there are only a subset of those that meet our immunologic criteria.
And then you have to do 2 more things. You have to ensure that they really do go to the cell type you want. IPS cells sometimes love going to liver cells and hate going to beta cells as an exam or heart cells as they say, right. They just they have predilections who would like to go. So the second is that you need genomic stability through that.
And the way that the field has generally looked at this in the past has been karyotyping, which is a little bit like trying to figure out if a patient has cancer by palpating their abdomen and there are more sensitive ways to do this and trust that we are doing them. That just takes time. And then we have to do the gene edits and then ensure that again we have a very stable, we have genomic stability and that gene edited IPS cell will go to cell type if you like. So it just takes time, it's very complicated and making sure that we have GMP reagents all the way through that they're very high quality given and we don't know a lot about the biology yet and that we have freedom to operate. And we're working on all of those.
And again, I feel really good about where we are, but it just takes time. And that's why with the IPS derived hypo immune cells, it will be a few years before we're in human testing. It's just because all of those things take time. Okay,
good. Maybe a broader question just about initial data. So let's just, for sake of argument, assume with both Fusogen and hypoimmune, you can file an IND sometime next year and maybe in 'twenty 3 or maybe it takes a little bit longer than that, you have some initial data. How do you think about that initial data in terms of, let's call it, derisking the overall platform? Like what does that do in terms of demonstrating safety or efficacy or just delivery across those platforms to then allow you to maybe move more aggressively across a range of different biologies?
Yes. So
I would say, so that gets at where is their correlated risk, right, in some regards, right, because correlated risk, say there's correlated upside too. So with the allogeneic T cell program, the question is, have we really nailed the ability to hide cells from the immune system? Ultimately, that is the question. And there are 2 separate questions in there. 1 is, when you do that to an allogeneic CAR T cell, do you see a meaningful clinical benefit in terms of durability of response?
And that will define how valuable what we're doing is in the oncology field, right? We're behind and if it turns out that they live longer, but it doesn't matter, then that's a lot of work for not a lot of effort, right, a lot of upside, I should say. But the flip side of that is, if they live a long time, what you've done is you de risk the whole platform, right? And so now when you think about the beta cell program, your probability of success goes way up. All of the other glial progenitor cells, all these things that we're trying to hide from the immune system, they really do change in terms of how you think about it.
So really, you are going to get your 2 questions that come out of that. 1, does it matter clinically? Does it happen? And if it happens that they live longer, then the whole platform becomes more valuable. And then does it matter clinically, which then will tell you how valuable the Allot program is.
So then on the Fusigen platform, what you're really asking is, can we deliver enough? This works. We can deliver payload in vivo in a relatively cell specific way. It's really can you do it well enough, right? And so I think to the extent that you can, you get more comp and that you can manufacture at that scale, right?
You get more confident that these other cell types are going after and we'll figure it out. We'll get there, right? And again, I think that in and of themselves it will be very valuable If you can show you a single injection, no conditioning chemotherapy, nothing else, 1 treatment and a patient might have curative cancer therapy, was really hopefully very limited toxicity. And ideally, no nothing more than what you get from a CAR T cell, maybe even less than what you get from a CAR T cell in CRS and neurotoxin, that's right, might be worse. You have a really important drug for really generalizing accessibility to patients.
So that would be so I do think that they will have they're very independent platforms and they're very independent in terms of the risk. But within each of them, they will read through to multiple programs. If you fail, you will say, boy, you got if it doesn't work for T cells, say, how is that ever going to work for islet cells, right? We've got some real thinking to do.
Yes. Okay, good. So Steve, maybe in the last couple of minutes, we could just touch on some of the, I guess, what should I say, more far out stuff that you're doing, maybe some of the cardiac regeneration work that you're doing or otherwise. I'll let you pick sort of what you think is most interesting. But maybe just give people a view into some of the other stuff you're working on.
It's always fun to talk about some of them just made a little bit of progress and that maybe people haven't paid that much attention to. So cardiac is a good 1. So the idea here is that still if you go through all this, the number 1 killer in the world is heart disease and heart disease is worse than all cancers put together. In the United States, they run neck and neck every year. And there really have been very limited novel medicines, right?
And the problem is for most patients who have congestive heart failure, it's a disease where the cells are just gone, right? So you've had a heart attack, they're not there yet. And so they need to we need to put them back. And the challenges are 3 fold. You need to put in cells that engraft and function, right?
You need to hide these cells from the immune system and you need these cells to integrate with the electrical conduction system of the heart. And in particular, what we've seen is that that first few weeks there's a real risk of an arrhythmia. And we've shown you data that says, hey, we can put cells back into a monkey and that monkey will get largely recovered to almost normal heart functions and a small end, so be careful with it. But they clearly recover at least meaningfully. We've shown through data from our hypo immune platform that at least in certain studies we can hide cells from the immune system.
So what we recently showed was that through a series of Chuck Murray did through his lab is that we can make a series of gene edits, some turn on, some turn off and you make these cells, they no longer are arrhythmogenic. And they integrate with absolutely no issue around arrhythmias. So what we haven't shown is that they function as well. We have to show that over time. We've shown them in graph, but then we've shown they function, but we need long term function because you are knocking out some pretty important risk.
Most of the time I think about all these ion channels and hearts being there for a reason. And so we still have that to do. But I look at that as a really good example of a hard problem that we tackled head on and where through really a combination of rational design and a little bit of luck made some substantial progress over the last few months that could lead to a really great drug, which again, if all went well. That will take a bit more time for us to enter into human testing. But all those edits in, it would probably be, again, a few years out, but something that I would say is very exciting.
Okay, great. Well, wonderful, Steve. Thanks for being here. Thanks for spending some time with us.
Always a pleasure. Great to see you. And thank you, everybody, for your time today. Appreciate it.