Good afternoon, everyone. My name is Daina Graybosch. I'm a senior equity research analyst here at Leerink Partners, and I'm excited to be hosting Century Therapeutics, a company that I've had the pleasure of covering with the VP of my team, Jeff, since their IPO several years ago and seen the company through multiple transitions. You know, sometimes you get married to a company, and they don't change very much, and you know, it sort of gets to be the same. This company's changed a lot, and we're actually did something really exciting, and it's been a pleasure to dig in and understand this more. Thank you for joining us, and I hope everybody here can learn a little bit more about what you're doing today as well. I'm joined by Brent, the CEO, and Grant. Whom I've met for the first time today, so I thought maybe we'd start with just maybe Brent and Grant, a quick introduction. Both, you've undertaken a very different strategy, so if you could just quickly tell us what that is. Grant, I'd love to learn maybe a little bit more personally about you as well. Yeah, sure. Grant, you want to start off with your intro? Sure. Well, it's a pleasure to be here. I'm Head of Research at Century Therapeutics. My background is it all started with iPSCs with Rudolf Jaenisch back at the Whitehead Institute. This is sort of a full circle moment for me because I was there at the time that iPSCs were first discovered right around Yamanaka as initial paper. Did a little stint with T cell editing at Editas Medicine as one of the early scientists there, and then helped to build Clade Therapeutics with Chad Cowan, and that's how we joined Century Therapeutics was with the acquisition back in 2024 and really excited about the progress we're making and some of the exciting opportunities we have this year. Great. Thanks, Grant. I'm Brent Pfeiffenberger, CEO of Century Therapeutics. I should just maybe a quick reminder before we get started is we may make some forward-looking statements today, so just remind everyone to take a look at our most recent public filings for the most recent risk factors and uncertainties. Daina, I'm happy to start with the transformation and change, but would love to have you guide me on what I'd like to hear next. Yeah. I mean, the recent announcement was that you're taking your iPSC platform and directing it, or have already directed it, and you've unveiled it to us towards beta islet cells and type 1 diabetes. I wonder if you could talk about why you undertook this change. You have, at Century, taken a number of pipeline and platform changes over the years, you know, pursued them a little bit and then moved on. Why should we have confidence that this is the right opportunity, right cell type, right edits this time in this pivot? Yeah, look, I think it's a great and very fair question. I'm happy to give the best context I can give behind it. Look, I think there's probably two questions in that I should try to address. First, why were we interested in type 1 diabetes? Then I think the second, you know, why are we confident that it's the right bet to make? If I take everyone back a little bit in time, you know, I joined Century a little over two years ago, and, you know, very, very early within my time at Century, you know, at some point, we were running close to 11 or 12 preclinical pipeline programs in parallel. We've always been focused on iPSC-derived therapies. We've always been focused on immune evasion strategies. That work and that parallel work we were doing on those preclinical programs gave us some really unique insights as to how different cell types, how different targets, how different engineering strategies on immune evasion stacked up against each other internally and how we felt they compared against some of the external datasets that were available. From that work in March 2025, we came out with a more formal pipeline prioritization. We narrowed that down to around four core programs at the time. As much as we were excited about the profiles of those programs that we prioritized publicly, we were also not naive to the fact that, one, some of them were in some very competitively dense spaces, and two, there were others that we knew just based on the complexity of the target or therapeutic area we were going after, they were gonna take more of a developmental timeline to get there. It was at that, you know, same piece of strategic work where we asked ourselves, "What is another therapeutic, you know, program we could go after that meets a different set of criteria?" That set of criteria we looked at specifically was, one, we want an area that was less competitively dense. Two, we wanted to make sure there was clearly medical unmet need and a bigger commercial opportunity for the program. Three, we wanted to make sure there was a very well-established clinical profile that was out there, a proof of concept. Four, and this is the part that's hardest to measure, but wanted to make sure we felt we could leverage our unique platforms and knowhow and move at a pace that others can't move at. When you look at type 1 diabetes across those parameters, and I'll try my best to quickly summarize, what got us excited is let's start with, you know, the first on competitive density. I'd argue that based on what we're trying to do and trying to accomplish, there's probably only two other companies that are within kind of the same frame that we're operating in and what we're trying to approach and what we're trying to do. Obviously, clearly, we believe less competitively dense. Second, around unmet medical need and commercial opportunity, there is two million or more probably at this point in time, type 1 diabetics in the U.S. alone. I think interestingly in this space is if you look at that two million patients in the U.S., about 1.3 million of those patients are what you define as uncontrolled by HbA1c. Even more interesting is you look at the patients who you would define as controlled, they still typically have these comorbidities or long-term comorbidities that really plague this disease, things like diabetic neuropathy, nephropathy, cardiovascular disease. There's this really big unmet medical need among this really big population of patients. All right. Check on the second criteria. Third was, is there an established proof of concept clinically out there? What's fascinating about the type 1 diabetes space, and what we're trying to do is there is 20+ years of experience using cadaveric beta islet transplants that shows very clear clinical proof of concept that essentially you can functionally cure these patients and free them of exogenous insulin use. Now, the problem with that approach has been two things. One, cell source, right? Cadaveric islets are not an easy thing to get and scalable. Second, the fact that, I'm sorry, just lost my train of thought. But anyway, the proof of concept, there was very good clinical data, right? Some of the data centers that follow this data longitudinally, that do these transplant surgeries, you can see out 15, 16, 17 years patients that are still free of exogenous insulin post-engraftment if they can tolerate the chronic immunosuppression goes along with it. We felt very good about conceptually there being really good data to support this. The final piece was around our capabilities and know-how. You know, we're obviously a company that knows cell therapy really well, but we also know iPSC-derived therapies really well. I think what's unique about Century is we have individuals like our CSO, Chad Cowan, who's got 20+ years of experience on beta islet cell work. We've got folks like Grant, who's sitting with me here today, that's got 10, 15 years of work on iPSC-derived therapies. There's just some very deep, unique know-how and insights that we felt could help us move at pace. That was really the rationale sitting behind it, why we got excited about type 1 diabetes. I think in a very short amount of time since March of 2025, we've moved at an unprecedented pace to get to a drug candidate into enabling studies and I think initial proof that the bet we've made is the right one so far. Let's talk about the product profile. I think in our recent work and thinking about this, I haven't thought about it in several years, but I used to. We gotta get a productive and durable islet cell therapy to meet that unmet need. You have to overcome some barriers. You need strong, consistent insulin release function, you need manufacturing scalability, and you need to be clinically durable with as minimal immunosuppression as possible. Do we have those three major buckets correct, and which of those barriers do you think is most challenging, and which do you think you have a unique approach to overcome? Yeah, I think those are on target, Daina. I mean, I think we think of it very similarly. I think there's kind of one bucket around just are you producing the right cells, and can you get them to engraft and function properly? The second, you know, similar to what you mentioned, is this burden of having to give chronic immunosuppression to these patients and the, you know, side effects and challenges that come along with it. Then three is it really is a scale and supply issue. You've got two million patients out there with type 1 diabetes in the U.S. alone. If you believe you're on a path or a line of sight to functionally cure those patients, you need something that's more highly scalable to address that. I think one interesting way to think about it, kind of take it one step further is how you would think about what clinical transformation looks like around those parameters. What we've heard, I think, from the investigators and KOLs that we've spoken to is that there's really a few key elements that very much align with some of the challenges you've outlined and we're trying to tackle. One is you need to be able to remove the need for exogenous insulin. Like I think that is, you know, front and center, very clear. You've got to create that functional cure for these patients. Second is you need to at least remove the most burdensome aspects of that chronic immunosuppression. You know, I think in our conversations, the most prominent thing we hear is the burden associated with tacrolimus. Our goal is to go beyond that and potentially eliminate, you know, further the need for chronic immunosuppression, but I think that's the kind of baseline mandate. Third, as you've clearly pointed out, you've got to have a technology or scale or supply that can actually be accessible to this larger group of patients. I think we think very much in line with how you've outlined it. You know, as far as the challenge of each one, you know, I'd argue that, you know, the first around cell engraftment function is probably an area where there's just more proof of concept, right? Cadaveric islets have shown it. Vertex has now shown it with the use of their stem cells. You know, I think we feel very good about the profile of our cells pre-clinically. I think that's one that's probably more approachable and I think, less of a challenge. I think the bigger challenges sit in can you truly eliminate the need for chronic immunosuppression over time in patients and avoid the immune system dynamics? Third, can you really get to a scale that's going to be able to tap into millions of patients that are out there suffering with this disease? I wanna spend more time both on the scale and the chronic, immunosuppression, but maybe let's start with scale. Just to get a sense of the scope of this, can you tell us like how the islets are delivered to patients? How many cells do we need per patient? Will they be treated more than once? I mean, if you look at the history of beta islet cell replacement therapy, and you start with the cadaveric islet transplantation, they are always typically administered via infusion through the portal vein. So that's been, you know, optimized. It started with the Edmonton protocol. It's been optimized over those 20 years. I think they've got a very good procedure and way to proceed on getting successful engraftments using that approach. You know, as far as other routes of administration, there are some interesting data starting to emerge. Intramuscular is another area of interest. There's obviously much less data using this route of administration, but there is some good early clinical proof of concept on using things like direct rectus sheath, which is in the abdominal wall, as a potential ideal area for things like intramuscular injection of these replacement therapies. There's other routes of administrations that are being explored or thought about, but I would say those are probably the two that are more front and center, at least from the work that we've done. Yeah. Does that answer your question? How many cells? I mean, the number of cells, you know, I think the best data we have out there is probably the data coming from Vertex. You know, they were currently using 800 million cells in their ongoing program. I think based on the profile of cells that we're seeing at Century preclinically, we're probably somewhere in that ballpark, but we need to do a little bit further work and obviously have the right dialogue with the FDA and other health authorities around the final trial protocol. Do you think you have to dose people more than once? We will see. I mean, look, it'd be ideal to be able to have a one and done. I think the beautiful part about what we've developed technology-wise in these cells for Century is, and Grant will probably speak to this a little bit later around the approach we have for Allo-Evasion, you know, we have the ability through our IdeS technology and the ability to provide humoral immunity protection that if you need to, quote-unquote, top up or redose patients or re-engraft patients at a period down the road post initial engraftment, that's something we think is very feasible with our cells and may not be as feasible with other approaches. Okay, let's talk about manufacturing. I think at first glance when I heard this, I'm like, "Oh, you guys know how to scale up. It's iPSC, it's the same." The more I thought, "Oh, wow, this is really different." At least that's what the conclusion I've come to. Can you help me understand how differentiating a mature beta islet cell and scaling it up is different from iPSC than an NK or a T cell? Yeah. Whenever we embark on a differentiation approach, you know, you really have to start with the end cell in mind. I think one of the key differences between a beta islet aggregate and a T cell or NK cell is that at the end of the process, you're essentially with a non-proliferative cell. As you progress through the different stages of differentiation from an iPSC to that end aggregate, you're seeing less and less proliferation as you move towards that mature beta islet. If you are looking for cell numbers and scale, you have to really look at the front end of the process when you're thinking about a beta islet drug product. That's where you really have to put a lot of your emphasis when you think about scaling up to get those cell numbers. You're, you know, definitely looking at trying to increase your cell number at the iPSC stage, so that when you enter the differentiation process, you're already, you know, with enough cell number to achieve the type of numbers you need at the back end of the process. Different than NK and T, where those cells divide. Yeah. You differentiate, and then you just rely on their natural proliferative capacity. Exactly. I think you can find different points in the process to achieve scale and because there's different points of that process that have proliferation and expansion and fold expansion as part of it. That's just different with beta islet differentiation. Maybe on the differentiation for a moment, does differentiating cells at scale, is that a challenge? Like, you have to scale up and differentiate. Do you need a much more efficient process? Yeah, I think. A more sorting process to purify out? Yeah. The way I think about it is, the first step is to have a real understanding of what your process is. You really need to have good control over the process. You need to have defined measures of success throughout the process. The good news about the beta islet differentiation approach is that we have those. We have the ability to understand how we're doing as we march towards that final mature beta islet, you know, whether it be definitive endoderm or pancreatic progenitor cells. There are clear markers and guideposts that you can assess to determine how you're doing. By having control over the process and real definition at a smaller scale, that enables you to then figure out how to do that at a larger scale because you have all of the things that you need to determine success. Now, it doesn't mean that it's not gonna be challenging, and that's one of the things that we're really investing in, both from a people and money perspective, to get out in front of some of those key challenges that we know are going to be part of the scaling paradigm. In talking to others, we've heard, it's incredibly challenging to grow iPSCs, iPSC cells at scale, because it requires, and I think you'd agree, 3D suspension culture. Mm-hmm. Where you get differences in fluid dynamics as you grow up. You may have differences in access to nutrients as you grow up at a large liter scale versus- Mm-hmm. A small liter scale. Also that you get shear forces that change as you scale up that create genomic instability, and that's been very difficult to overcome. Mm-hmm. One, do you agree with the articulation of the issues? Two, what gives you confidence that you have a path there when Vertex and Sana and others have struggled? Yeah, I think you're spot on in terms of identifying some of the key challenges with, you know, scaling and culturing iPSCs in a suspension culture. The way I think about iPSCs, and I've been, you know, growing these for a very long time, is that iPSCs really develop those mutations when they undergo stress. If you can find ways to really reduce that, you know, the stress on the cells, you're really going to enable better culture, better stemness, and better overall genomic stability. I think that's the starting point to addressing any challenge is to understand what it is that is leading to those challenges. One of the things that we've been able to develop at Century is a really deep understanding of iPSC biology and how to assess iPSCs at different stages whether it's generating iPSCs, whether it's editing iPSCs or culturing iPSCs at scale. I think we have what we need to address those challenges. Now, it's going to be a stepwise approach to getting there. The good news is that the ecosystem has been looking at this for a long time. There are already some key lessons that we can apply to our own internal efforts and combining that external expertise and understanding and knowledge along with our internal capabilities. I think we have a path forward that gives us some confidence that we'll get there. Is this going to be a lot of small things or is there going to be like a big technology step change? Do you need that? It's a good question. The way I think about innovation, and it's particularly true when you're doing complex processes like differentiation, it's often the small things that actually provide tremendous benefit. You really need to have the right methods to understand what's happening to your cells. If you have the right analytics, then you can start to understand what changes to the cultures or changes to what scale does to your cells, and then that can give you clues to how you can solve for the issues you're seeing. I think it's a combination of expertise, good analytics, and then just some good old-fashioned problem-solving. It's sort of like in drug development. You can control the dose, you can measure a nice outcome, and that's because you know these cells so well and you have the right analytics, that sort of sets up a system to iterate, and that system gives you a lot of confidence that you'll find the right solution. I think you summed it up really well. Let's talk about Allo-Evasion because that's where Century and Clade have been focusing for so long. I think it's Allo-Evasion 5.0 in this program, and I think this program is CNTY-813. Do I have that right? You do. That's my sister's month and birthday, so that's good. What does it solve, and which elements are clinically validated in this 5.0 by prior programs, and which are more novel with more inherent risk? Yeah. The way we approach developing Allo-Evasion 5.0 is really starting with what are the immunological challenges that we need to address in order to protect our allogeneic cells, whether it be T cells or beta cells or any other cell type that you can differentiate from iPSCs. The three key aspects of the immune system that we've focused on are, one, T cell recognition, which is something that the field has been addressing for quite some time, and we're not taking any approach that's really radically different than anyone else. We're knocking out class I and class II to eliminate the ability to present foreign peptides to the patient's T cells. The second key challenge or key part of the immune system that is capable of rejecting allografts or allogeneic cells are NK cells. This is particularly sort of fired up when you knock out MHC class I as well. In Allo-Evasion 1.0, we started with HLA-E, which is a reasonable way to address NK cell recognition attack, but unfortunately, it only addresses a subset of NK cells. When we thought about how do you tackle the NK cell problem, we really wanted to identify a solution that would address as many of the NK cells as possible that exist in a single individual as well as across a population of individuals. We did a mini screen where we looked at a number of different knockouts and ligands, including a number of synthetic ligands that we designed against known inhibitory molecules on NK cells. Long story short, we developed what we termed CD300a TASR, which we think is the first of its kind that really is a pan-NK inhibitor with a mechanism of action that is really well defined by targeting an inhibitory ligand called CD300a that is broadly expressed on NK cells, irrespective of NK cell subtype or of population demographics, whether it be CMV positivity or different ethnic backgrounds, etc. This is all published in a paper that we published last year in Blood Advances, which describes the way that we developed the CD300a TASR and some of the in vitro data that really supports across 45 different human donors a lot of our confidence that it's a broad NK inhibitor. Then the third piece is around humoral immunity. It's been known for quite some time that in particular in organ transplants, allogeneic organ transplants, that antibodies are an important part of immune rejection. We have taken an immunoglobulin protease and tethered it to the membrane of our cells. This really blocks all antibody IgG-mediated cytotoxicity against our cells, whether that be complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity that operates through the Fc receptors found in NK cells and other innate cell types, and the third being ADCP, which is antibody-dependent cellular phagocytosis. It's really a holistic approach. We think it's the most holistic approach in the cell therapy field, and will address a lot of the key immunological challenges associated with allogeneic transplants. A couple follow-ups. On the humoral immunity, does that also prevent re-flare or the original disease process? Well, we certainly I think with type 1 diabetes, I think what you're alluding to is the fact that you have a lot of antibodies that are part of the etiology of the disease that have been part of losing the original islets in patients. I think it certainly is a benefit to have an immunoglobulin protease as part of our islet strategy because if any of those antibodies are still around and can recognize insulin, for example, you know, in the cells, you know, we believe that this approach could potentially block that type of recognition. It's IgG mediated? Do you worry about IgM, IgA? Yeah, I think it's a great question. The short answer is yes, that's something that's on our radar. I think one of the ways we're thinking about this is we're not stopping the innovation internally around Allo-Evasion. This is, you know, we know that we're gonna learn a lot from the clinical experience and we're gonna be prepared to address anything that we're missing as part of the first foray into the clinic. I think, you know, what we believe is that the advances we've made will be important for changing the patient journey. But we certainly are not gonna be complacent. The immune system has been working for years to try to deal with foreign cells or foreign viruses, and so we know it's a potent aspect of humans. We will continue to innovate as needed. The question everybody wants me to ask now is, okay, when do we see all of this? When is this in the clinic? Are there any remaining milestones for the IND filing? And when could we see sort of the first clinical data, both with light, you know, I assume you're gonna start with some immunosuppression, and then without immunosuppression? Yeah, look, we're still very much on track to submit an IND towards the latter part of this year. I think we had a very good recent engagement with the FDA around a Type D meeting. You know, the focus of that meeting was really around ensuring we had the right preclinical data package that we're putting together to enable that IND submission. You know, I think we've got very clear and positive feedback back from the FDA on what is needed and what is not needed, mostly in relation to things like tumorigenicity and final GLP toxicology studies. I'd say, you know, between now and submitting that IND, there's probably, you know, a few key things we've got to wrap up. One is the final package of tumorigenicity data and final GLP toxicology data. I think the other element is just making sure we've got the final clinical trial protocols that we can then bring forward to something like a pre-IND meeting with the FDA. Your second question around- Yeah. Timing of clinical data. Look, if you assume success on the IND submission and typical timelines in this space, I think we're very much on track for initial clinical proof of concept in the second half of 2027. Initial patients? Initial clinical data, yes. You're gonna run the study in the U.S.. You're not going to other countries to accelerate this? I would broadly say we're agnostic to geography and more focused on volume and expertise, but the U.S. clearly has a tremendous amount of expertise and centers we can rely on. Got it. Okay. Thank you. We got through a lot. Oh, yeah, of course. I'm sorry. David. You put some time into the Allo strategy. What about differentiation? What are you doing? I mean, how complicated is the differentiation protocol? Yeah. Does it come before your Allo strategy? The Allo strategy sounds like you're doing a bunch of editing. Is there a yield loss as a result of that? Can you talk a little bit more? Maybe I'll just repeat the question, which is, I think, essentially, how do you think about differentiation complex? What are you doing there in terms of innovation? Then how do you think about the engineering part of it in order to introduce the Allo-Evasion edits? I think one of the beautiful things about the iPSC platform is that we can do all of the engineering in the iPSC one time. We essentially select a clone that has the edits that we strive to make with a full characterization of that clone. That really provides a tremendous amount of control at the end of your editing process, and that really reduces a lot of the risks associated with editing. Once you have your clone, the critical piece, and I mentioned this earlier, that you really wanna have exquisite control over that process of differentiation. From the very outset of standing up this program, we had a couple of key sort of things that we indexed on. The first was we wanted to make sure from the very beginning that we had a 3D bioreactor enabled process that would you know, allow us to move to scale a little bit more quickly. The second was to make sure that we had all the right metrics and assays in place to really understand how we are doing throughout the differentiation process, and then at the end of the differentiation process. You know, for both our T cell program, CNTY-308 and for CNTY-813, our beta type 1 diabetes program, you know, one of the things we've really felt is critically important when thinking about differentiation is to learn what the human body tells us about how you make these cells, and you know, use that as a roadmap for normal human development, for essentially having the right differentiation protocol. I think that's what has allowed us to move very rapidly from March of last year to now. You have a lot of factors, not just line factors. I know you can't get into too much more detail, but. Yeah. We have a number of different iPSC lines internally that we've generated, and that's, you know, that are GMP enabled. Those are the starting point for any sort of engineering procedure. Because we already had those in-house, we were able to engineer quickly and then move through the differentiation process. Last question. Yeah. Do you have a cell now that releases C-peptide or TBD? In terms of our preclinical data package, what we've publicly disclosed is a combination of in vitro and in vivo data, using established, you know, well understood sort of methods for assessing beta islet function. Yes, we can produce human C-peptide. We can also rescue mice that have been made diabetic. I think we've publicly disclosed that we can rapidly bring mice back to normal glycemia after being induced to be hyperglycemic. We've got at least four months of persistence of our islets in those in vivo systems. These are NSG animals, so you know, we're not dealing with the mouse immune system in that context. These are well-established models for human beta islet assessment. All right. Thank you very much. Thank you for the additional questions, and everybody's attention. Okay. Thanks, Daina. Appreciate it. Thank you.