Hi everyone. The next speaker is Dr. Chad Cohen, Chief Scientific Officer of Century Therapeutics. Welcome.
Thank you very much. It's my pleasure to have an opportunity to tell you guys a little bit about Century Therapeutics, and I apologize in advance for standing between you and lunch, but hopefully we'll give you something to be excited about. Let me make sure I can advance this. I'm, of course, going to be giving you some forward-looking statements, and if you want to read the small print, there it is. What I'm excited to talk to you about is the continued evolution that we're having at Century. Probably many of you know Century as its ticker, which is IPSC. It's a company that's based in induced pluripotent stem cells, and the potential there is huge, right? We can essentially make any cell in the human body, and we've chosen to move forward with that platform with a couple of key things.
What we're really, really excited about is our ability to now accelerate what we think of as some core programs in the space. Many of you are probably familiar with our clinical programs, which are CNTY-101, which is an NK cell-based program with a CD19 CAR. That's in a sponsored clinical trial with Calypso 1, both here in the U.S. and in the EU. We also have an investigator-initiated trial, Caramel, that's working in Germany with Shetland-McAnthon, that we're also very excited about. Both of those trials are in autoimmune disease, and they're basket trials looking at sort of four different autoimmune indications. What I'm most excited about, probably because of my science background, is actually what's coming. We've got two preclinical programs which we're extremely, extremely excited about.
One is CNTY-308, which is in IND-enabling studies now and is actually planned to go into the clinic just midway through next year. That's actually our ability to, for the first time, make true, you know, sort of autologous-like alpha-beta T cells from iPSC cells, and that's again targeting B-cell-mediated diseases. A third program that we've been accelerating tremendously, which is our first ever non-immune cell program that, for competitive reasons, we're not talking about, but we believe has an incredibly high impact and is in a non-competitive space right now. All of this is powered by what I would call sort of our foundational science behind all of it. We have two things that we do extremely well. One is what we term our cell foundry, which is our ability to take those iPSC cells and turn them into truly adult functional cells.
Some of that is best highlighted by our ability to make, for the first time, any company has ever done this, real CD4 and CD8 T cells. I think the world knows that T cells work, especially in B-cell malignancies. They've also got these outstanding results in autoimmune disease. The struggle has been to make from an iPSC cell a T cell that really reflects that same, and I think we're the first of its kind making a truly comparable T cell, but now from an iPSC cell. Now it has the ability, of course, to compete in terms of cost of goods. The other thing that our deep expertise and our ability to understand the developmental pathways means is that we can actually explore many different lineages. If you think of us as just an immune cell company, you're probably thinking wrong.
We can probably make any cell type in the human body, and some of those cell types, when combined with the next area of real expertise that we have, can really make an impact in disease. The other thing that I'm excited about is we're, hands down, the industry leader in what you might term alloevasion or immune evasion. When talking about allogeneic cells, you have to start thinking, how do you protect those from the patient's own immune system? We've invested in this space for a long time. Personally, I've been sort of chasing this for over 14, 15 years.
Many of those inventions have seen the light of day in other companies, but it's at Century Therapeutics where this history has sort of seen its full evolution from alloevasion 1.0, which is actually embedded in CNTY-101, all the way through alloevasion 5.0, which is embedded both in our alpha-beta T cell program, the CNTY-308, as well as our programs, the non-immune cell program. We've also, as we've continued to evolve, undergone a restructuring of the company, which has really got us focused on the right assets and has the right number of people and the right things to sort of move the company forward, and that's extended our cash runway considerably. We're able to actually see the data returns on what we're talking about. We've got cash through 2027.
If we move into some of the science, which is what I'm most excited about, this is our pipeline now, as I mentioned, 101, 308. We also have some additional T cell programs, and perhaps what I said we're most excited about is this non-immune cell program. All right, giving you some more detail on our alloevasion, Century Therapeutics was really the first company to take something that was genetically edited to protect itself from the immune system and put it into patients, and that was done under the CNTY-101 with alloevasion 1.0, which essentially has three different gene edits that are in the cells, that are in all of the cells that are delivered to the human, and those remove the ability for T cells to attack the cell, and that's through taking out beta-2 microglobulin and CIITA.
They put in a non-polymorphic HLA, HLA-E, which provides protection from a subclass of NK cells. What I'm particularly excited about is our continued evolution in this space to, like I said, the industry-leading holistic protection against immune attack. We use the same sort of core edits to remove the HLAs from the surface. That's beta-2m and CIITA. We have two new industry-leading additions. One of them is the CD300A “taser,” which has been published on, and we've shown extensive preclinical data on, which is a one-of-a-kind defense against NK cells. Unlike all of the other NK cell-mediated defenses, this one doesn't hit a subset of NK cells. It hits all of them. It's the first of its kind universal defense from NK cell-mediated cytotoxicity, and we're extremely excited. In fact, its data is as compelling as cells that have their HLAs intact.
In other words, cells that are normally overlooked by NK cells. That's how good the taser is. Another unique feature of our alloevasion 5.0 is the first of its kind humoral protection. Most of you know that it's not just cells you have to worry about in terms of rejection, but it's also antibodies. This actually has an IgG-degrading protease tethered to the outside of the cell, which is able to protect against antibody-mediated immunity. This alloevasion 5.0 is built into all of the preclinical products that we're talking about, and I'll get to some of those now. This is just giving you some of the highlights on it. Like I said, the taser is naturally one of the, it's a synthetic ligand that takes advantage of a natural pathway. This is a pathway that all NK cells have.
If you look over on the right with the CD300A, it's the only receptor that's actually expressed in all NK cells across all the patients that we've ever looked at. What it normally does is it sees dead or dying cells as a result of flipped phosphoethanolamine and serines that happen on the membrane. That's its natural ligand. We hijack that by making a synthetic ligand that basically sees the same receptor, tells it it's seeing that signal, so that it skips over cells. It normally is used to skip over dead and dying cells. It now skips over the cells that have the CD300A “taser,” and you can see that on the bottom. It outperforms the technology that I pioneered earlier, the CD47, across the board.
It is far better at protecting against NK cells and all NK cell subtypes than even what you might call other leading technologies that other companies such as SonaBi Technology are using. The IgG-degrading protease is also a unique asset. It's the first of its kind, and it completely eliminates antibody-mediated removal, especially by IgGs, by clipping those IgGs at the hinge region where it removes the FC fragment, which catalyzes all of the immune reactions, whether that be complement-mediated cytotoxicity or the antibody-dependent cellular cytotoxicities that happen from either NK cells or phagocytes. You can completely eliminate them by the tethering of this enzyme to the outside of the cells. Like I said, best-in-class protection of the cells as a result.
When you have that, it really means now you can make cells that could do something particularly special because you've now solved the putting the cell into anyone you want and the persistence of that cell in the face of the immune system. That gets me to our next program, which we've got a lot of enthusiasm around, the alpha-beta T cell program. Just to remind all of you, the CAR T market is big, and it's growing. The major sort of problem with the market is actually the ability to make something that is cost-effective. Both the cycle time by using autologous products and the inability to make something that is a bespoke product in autologous CAR Ts that is cost-effective is what holds it back. We think that we've got some major advantages. Being an off-the-shelf medicine, you've got obviously improved time to treatment.
The manufacturing progress really gives us that ability to reduce the cost of goods, and you don't sacrifice anything in terms of the efficacy, which is what the next slides are going to show. We've got cells that actually perform on par with what you're seeing from an autologous T cell. For the first time ever, you can now deliver essentially the same medicine to everyone and have it ready when you need it. This is what we've built. We've got a cell that is, again, genetically modified to have the alloevasion 5.0. It has two other genetic modifications that are important. We've removed the T cell receptor so that you can get no graft versus host disease. It's protected from that sort of potential. We've added the CD19 CAR to that. It's, again, targeting any CD19 positive, typically B cells or early plasma cells.
I think the most important thing to say here is that it's got really comparable efficacy across the board to what you see in autologous, and I think this slide highlights it best. When you think about a primary CAR T cell, what you want to see in those cells is the ability to engage target, kill the target positive cells, but also increase the amount of the cells that you make. What T cells really do that is incredibly attractive is they exponentially divide upon target engagement. That's been the real downside of all the other sorts of approaches. We're the first of its kind that has exactly that same benefit. When we engage target, you get the same exponential division, and that's driven a lot of the times by the ability to produce your own cytokines.
If you look head-to-head here, primary CARs secrete a lot of IL-2 upon target engagement, which is what drives that proliferation. We secrete comparable levels of IL-2 upon target engagement. They also don't require any exogenous cytokines for this proliferation. Unlike other companies that are sort of putting those in on the backbone behind their cells to keep them going, we don't have to. That means that the cells can do really long-term killing, more than 10 rounds in vitro. They can persist in the blood in our preclinical models well more than a month, even up to two months. Perhaps most importantly, you can get complete tumor control. This is due to the fact that we have a proprietary differentiation process that makes not just a CD8 cytotoxic T cell, but also the CD4 helper T cell.
It's that unique mixture of CD4s and CD8s that actually drives the long-term durability in autologous CAR T products, and we make cells that are just like that. What's really nice is ours are tunable. If we need to turn up the amount of CD4s so that you get more helper function and longer-term persistence, we can do that. If you want to turn it down and you want to have more CD8s that are more cytotoxic, we can do that as well. This is what those cells look like when you put them in, and again, head-to-head with primary CAR Ts. They're just as good at killing. They're just as good at secreting the IL-2. What is perhaps most important is they're just as good at dividing in that exponential phase. You actually can get more than tenfold expansion of the cells upon target engagement.
Of course, that translates to in vivo performance. This is a tumor model where you're using NALM6 cells that have been put into mice, NSG mice, and it's a very aggressive model. The mice typically succumb within as few as 14 to 15 days and are definitely gone by just over two weeks at 21 days. When you dose those mice with T cells, primary T cells, you're able to completely eliminate that tumor and sustain those mice. The same is actually true when we give them our iPSC-derived T cells because they have very similar function. We not only have similar function, we have similar sort of, you could say, PK characteristics. The cells actually persist in the blood. In this case, they were actually at higher levels and persist for just as long and remain at higher levels.
One of the most exciting to me is on the far bottom right, the cells remain active. We actually re-challenge at 27 days these mice that have now are tumor-free with new tumor. What you see is you're able to reactivate the cells and have them continue to keep the cells, the mice tumor-free. In the green is our cells, and in the blue is primary T cells, where about half of the animals actually succumb to the tumor that you've given them, and about half of them are able to keep up. Not only are the cells as effective, because of the control that we can have either overdosing or the ability to put the cells back in, you can actually make them even more effective.
I did want to make sure that I also covered our current clinical program, which is CNTY-101 and NK cell, our CAR NK cell-based therapy with our alloevasion 1.0. This is our current clinical program, and as I mentioned, it's in two different clinical trials. The company-sponsored trial, which is Calypso 1, which, as I said, allows us to recruit a basket of patients in autoimmune disease. That includes lupus, lupus nephritis, myositis, and scleroderma. The structure of that trial is that we have the ability to dose the patients twice if we want to, because one of the nice advantages of having an alloevasive product is we can re-dose it. We don't have to worry about it. We're actually even re-dosing without lymphodepletion in the second dose of our own company-sponsored to sort of show where it's going.
In the investigator-initiated trial with Shetland-McAnthon, they took a look at our data, and they took a look at what was happening with other patients in their site. What they decided to do was a single dose, because in their opinion, all they needed to see was the depletion of B cells for about 30 days to get where they wanted to in outcomes. That's what they're doing in their particular trial. I think why all of us are excited is because we've got real key proof points from an earlier trial we ran in B cell malignancies. I wanted to, of course, highlight what we think are some of the real opportunities here. I think that this is a sweet spot for NK cells. NK cells are actually not an extremely long-lasting cellular product.
Their ability to rapidly eliminate B cells, but not stick around and lead to B cell aplasia, is actually an advantage in this particular case. We can make these cells at very low costs of goods, in fact, approaching what I would say antibody-like costs of goods. Perhaps they're the safest cell therapy. Unlike T cells where you see a CRS-like response, which they're calling LIKATs, probably due to some of the expansion, et cetera, there's been an incredible safety profile in NK cells. A lot of those combinations we think are stacking up to make this look like a very attractive product. As many of you know, the real hurdle is providing long-term drug remission-free. We're looking forward to updating everybody on our trial outcomes by the end of the year. We've been recruiting patients in both of those.
We've got patients on trial that we're taking data from right now. It is, you know, hopefully going to read out in a way that all of you get excited about. We also know that showing you like a one-month data, two-month data on one or two patients isn't as compelling as actually looking for drug remission-free at sort of the three and six. We're sort of holding the cards until it's the right time to play. What gives us a lot of confidence is what we already know, what the NK cells do in the B cell malignancy trial. At the dose that we're using them in the autoimmune trial, as shown here on the left, we get really deep, sustained B cell depletion for up to 30 days. In all of the patients that were dosed, we see complete elimination of B cells in circulation.
We can also see that those B cells, when they do come back, re-emerge in that sort of naive fashion. You get the so-called B cell reset in the patients. That, again, is a nice proof point for getting the type of on-target efficacy that we hope to see from the NK cells. Perhaps most importantly, unlike the antibody products, we actually see real deep tissue penetration. This is from our B cell malignancy trial, but we're actually able to see these in the lymph nodes, seeing activity of our own NK cells. That's where they're going. We know that you can expect where the site of action is, especially in autoimmune disease with these B cell regulated diseases. We can get our cells there, and our cells can be not just there, but active. Perhaps most important for all of it, our alloevasion works.
This is just showing you under the cover of lymphodepletion at the very first sort of dosing, you can actually see that our cells achieve a peak PK and then come down about a week later. As the lymphodepletion actually wears off and you get a return of T cells and NK cells in the patient, you can see that there's no change in the PK profile. The cells are capable of actually having the exact same PK independent of the cover of lymphodepletion, meaning that, in fact, just like in a test tube when we test the alloevasion, it's actually working in the patient to give you this enhanced persistence without lymphodepletion, which is really promising in our opinion as we start to think about using this in autoimmune diseases where lymphodepletion is more of a problem.
That's just a summary of where we're at as a company, and I'm happy to take any questions, and I'm extremely happy to be able to present today.
This year's data readout that patients from Calypso and Caramel are only Calypso.
I think that the intent is to aggregate all of our patient data, and we've been enrolling on both trials. The difference is, of course, we don't have full control of the data release from our investigator-initiated trial. It's going to be whether or not those investigators sort of feel comfortable with the release at the time when we plan to take the data from Calypso.
For Calypso, are you seeing all four diseases or just one or two of the diseases?
We've been recruiting agnostically across all of them. I think we'll give you a cut of everything we've seen that's matured across everything we've recruited. Since we haven't released what we've recruited, who we've recruited, and what diseases, we'll have to all stand.
Is there any expectation for numbers of patients?
I don't think we've guided towards any expectations.
Based on the alloevasion, do we necessarily need lymphodepletion? Is the idea that maybe we can go without lymphodepletion just like CAR T is trying and some are doing it with just cyclophosphamide or bendamustine?
We are not sort of blind to that. In fact, in our study design, we have the ability right after the first several patients to go into a lymphodepletion-free or lymphodepletion-reduced trial design. I think that is something that we plan to explore because we think that with alloevasion, that could be a big advantage for us to either soften or reduce or even eliminate the lymphodepletion that people are using.
For first-gen alloevasion B cells, is the insertion versus the next-gen is the NK gen? Partial lymphodepletion B cells are not intuitive by the course?
It depends on the patient. HLA-E is a ligand specifically for NKG2A, which is the inhibitory receptor. In patients that are young and not virally experienced, they can have up to 90% of their NK cells be NKG2A positive. In most of us, like me, it's going to be more like 50% or 40%. That means the remaining 50% to 60% of NK cells aren't inhibited by something like HLA-E.
Okay, that brings us to the end of this session. Thank you very much.