Thank you all for coming to the 45th Annual TD Cowen Healthcare Conference. I know it's first thing on Monday morning, so we're getting ready to go. It is my pleasure to introduce CEO of Generation Bio, Geoff McDonough. Thank you so much. Thank you, Brendan, for the invitation, for the kind introduction, and most of all for the entry track with Van Halen, which speaks to my '80s heritage that was outstanding. Very excited to be here today to talk about Generation Bio. We're here changing what's possible for people living with T cell-driven autoimmune disease. What I'm going to do today is walk you through where the company is today and our strategy to profoundly change this very important aspect of the immune system and driving autoimmune conditions. We're a public company, so keep that in mind as you listen to our statements today. What we're talking about here is targeted siRNA therapeutics to combat T cell-driven autoimmune diseases. It's essentially the combination of highly selective delivery, which we accomplish with our proprietary cell-targeted LNP delivery system. On the payload side, using siRNA to hit undruggable T cell targets. What's important about siRNA, of course, as we're very well known, is the ability to address intracellular targets with genetic precision and to achieve very predictable pharmacology. The company is focused on entering the clinic in the next 18 to 24 months. We're planning for an IND in the second half of 2026, and we'll announce our lead target and program around mid-year this year. All of this work sits within our cash runway, which extends deep into 2027. This is a critical period of execution for us as we apply the platform to our first turn towards the clinic. The idea of opening a new tissue for delivering a validated payload such as siRNA is not new. We're building on a series of waves of tissues and cell types becoming addressable with this very well-validated technology. For us, of course, that means opening T cells for selective delivery of siRNA for the first time. This is quite a special achievement, which I'll talk about in this presentation. It builds, as I said, on the heritage of similar moves in the past. Dyne and Evity have made this move targeting skeletal muscle. Allemann began this really revolution in nucleic acid therapy in the liver, and more recently targeting additional tissues such as the eye and the CNS. Now, the autoimmune space is enormous. The number is huge as a market segment. Most of the top 20 drugs in the world are aimed at addressing autoimmune disease, and they mostly have centered on addressing aspects of the adaptive immune system. Many of them are focused downstream at specific cytokines or in a narrow way at B cell biology. In one aspect or another, they are either limited on efficacy because they do not address a fundamental aspect of the way the immune system dysfunctions in autoimmunity, or by addressing off-target cell types and therefore being limited or constrained by toxicity or off-target effects. T cells are an incredibly attractive target in this landscape because they influence so directly both the adaptive and the innate immune system. We think they are a really fertile target for that reason. When we look at the landscape of companies who are working in the autoimmune space, we really find ourselves in a protected white space for reasons that I will get into, where the idea of going after intrinsic T cell targets is one that is relatively new and sparsely populated. In fact, we can't identify a company today who's able to marry selective T cell delivery with siRNA as the payload. Plenty of companies working hard at using T cells to delete B cells. That's a very narrow B cell kind of strategy. Those that are working on targets that cut across many cell types, such as antibodies or degraders or small molecules, are not selective in their engagement of targets in T cells. What I think is special about this approach that we're bringing to bear here is the combination of T cell selectivity and the ability to hit intracellular targets with genetic precision. What I'm going to do in this presentation is walk you through the two aspects of our approach here to autoimmunity. First, I'll talk a little bit about what's special around our selective T cell delivery system using our cell-targeted lipid nanoparticles. Just to say at this point that the focus on T cells is to bring the company to the clinic with our first programs. As I'll talk about at the end of the presentation, this is a platform that allows us to direct delivery to very specific cell subtypes over time. On the other hand, it's this ability to address intracellular targets with genetic precision with siRNA and achieve a level of pharmacology that's quite different and differentiated from what's currently possible with antibodies. Before I dive into the delivery system and siRNA, I just want to give some perspective to what we're talking about when we talk about influencing the role of T cells in autoimmunity. We're really aiming at influencing the journey that describes how a naive T cell in systemic circulation in spleen and lymph nodes undergoes activation, proliferates, ultimately differentiates into a subtype of T cell, infiltrates the tissue, and sets up inflammation and damage in the tissue bed. This is a journey that underlies most of the current autoimmune diseases that we have therapies for and many for which we don't yet have effective treatments. What's interesting about this space, when you talk about addressing T cells selectively, is that a lot is known about the targets that influence this journey. It's just they've never been fully exploited from a drug development perspective. It gives us a nice head start to understand how, for example, T cell receptor signaling can be influenced both at the membrane or in the myriad of signal transduction proteins. Too for metabolism, the underlying mechanism by which T cells expand so dramatically, and they're alone in the human body in their ability to expand as dramatically as they do, depends on the upregulation of an enormous number of metabolic pathways that are broadly expressed in other cell types. A lot is known about these, but if you can't hit them only in T cells, they're not easy to exploit from a drug development perspective. This is true also for the transcription factors that drive differentiation of CD4 effector cells into Th1, Th2, Th17, et cetera. Of course, the same applies to targets that drive infiltration and local inflammation. It's this local inflammation that drives the set of therapeutic areas that are driven by T cells primarily. This is an example of four out of about a dozen, as I was saying. When you look at them, whether they're in the skin or the blood vessels or in the intestines or the liver, they are disease areas that you'll recognize are not well covered or addressed by the current focus on B cell therapy, whether by CAR-T or by T cell engagers. These tend to be diseases that are not well addressed by a specific or narrow B cell therapy. What we're looking for here as we make our target and first indication selection is the novelty of a target that can be selectively hit in T cells, which has a really strong and well-understood basis for its biology and a really good link to the indication that we ultimately want to pursue to begin with. Of course, what's great about all of these targets is that they can address a portfolio of indications. Wherever we start from an indication perspective, we'll be able to expand based on a single target and drug product. Now I'll start off by getting into the delivery side of our platform, and then I'll turn to siRNA. Our cell-targeted lipid nanoparticle system is driven by dialing out nonspecific biodistribution with our core stealth composition and then dialing in specific cell targeting with a biological ligand. I'm going to take a few minutes on this to walk through why this is so different. In fact, it's unique in the landscape of non-viral lipid nanoparticle delivery. The core stealth particle is the essence of our delivery system, which prevents the engagement of serum-binding proteins with the LNP. Serum-binding proteins are what drive the passive biodistribution of all current LNP systems. What we do with that base system is use a ligand to dial in the specific cell targeting that we're aiming for once we've avoided the interaction with serum-binding proteins. We have created a set of bioconjugation chemistries that preserve the stealth activity of the molecule and allow the ligand to be presented in a very specific way to get to cell types of interest. As I was saying earlier, this system is modular. It is reducible in vivo, and it is compatible with a number of nucleic acid cargoes. Just to take that one click deeper, all current LNPs that we're aware of, either in the clinic or in development, are subject to the binding of serum opsonins. These are proteins in circulation that cling to the surface of the LNP and ultimately drive its uptake. The reality is that 99% of every administered dose of current LNPs ends up cleared by either the liver or the spleen. They have a half-life of minutes, usually less than 15 minutes, which means that there is a very limited amount of LNP available for targeting tissues beyond the spleen or the liver. This creates a background of both limited potency and non-selective uptake. For nucleic acid cargoes, this is incredibly important since the potency of the cargo is usually at the limit at this stage in our development, and the off-target effects are not something that should be ignored or something that should be minimized. In this paradigm for LNP biodistribution, that is not possible. In fact, it is the opposite of selective delivery. I am going to start off by showing what happens with our stealth composition without a ligand in the serum of non-human primates. What you can see here is that we've flipped this ratio almost entirely. We're delivering less than 1% to the liver and the spleen and other off-target tissues, leaving a very substantial amount of the LNP present in circulation. This is what I meant by dialing out non-specific biodistribution. As a consequence of that, we have a half-life of hours. What you're seeing here in mice is a half-life of about four hours, and in non-human primates, over seven hours. Dramatic extension of the availability of our targeted LNP. This data has been recapitulated with the ligand in place to engage our target cell type and only our target cell type. That means we have this large pool of LNP, as I was saying, and highly selective uptake, which, as I'll say in a couple of slides, also translates to potency, again, really important for nucleic acid cargo. Building on that background, I'll show now data in humanized mice to show that we're able to get over 90% of targeted T cells transducing our cargo with a single dose. That shows that we are taking advantage of that potency and selectivity, and we're not biasing in this specific ligand example between CD8 and CD4s. Moving to primates in the middle panel, you can see that our delivery is entirely driven by the ligand. When the ligand is not present, we get zero or low uptake in the T cells of interest. When we show or when we add the ligand and do the experiment again, what you see is you get very strong delivery to T cells. In this case, we're showing subtypes of CD3, CD8, and CD4. Going back to dialing out that non-specific biodistribution, I'm showing here in primates off-target biodistribution to monocytes, and you can see that the uptake there is negligible. This is a representative cell type. We've recapitulated this in B cells, myeloid cells, as well as in other parenchymal cells, as I showed you in the prior slide. This is the essence of what we mean when we're talking about highly selective delivery and why this level of selectivity opens up that broad set of targets in T cells that otherwise can't be effectively hit because of their expression in other cell types. Now, moving on to siRNA, it's well known that conjugating siRNA to sugars or to monoclonal antibodies or antibody fragments is effective in delivering at a level of potency that matters siRNA to liver, muscle, and CNS. It is not a stretch to wonder why you can't get siRNA to T cells. It turns out that T cells for the last decade and a half have been an enduring challenge for siRNA delivery. Whether it's difficulty in transducing enough material across the target receptors in the T cell membrane, or whether it's the concentration that can be achieved in the endosome or the degree to which the endosome allows si to penetrate the cytoplasm, the reality is that T cells and other immune cell types have resisted all attempts to reach them with conjugated siRNA delivery. Our thesis was very simple. Our ctLNP system, as I've just shown you, is highly selective, and it's engineered to drive endosomal escape. In other words, to open and fuse with the membrane of the endosome and discourage the contents of the endosome into the cytoplasm. Our idea was that our non-viral delivery system should be an ideal modality to solve this challenge for siRNA delivery. When we look in vitro, we see that it does. When we use a tool molecule against beta-2 microglobulin in vitro on the left panel, delivered in vitro with our ctLNP, you see very potent complete knockdown of this highly expressed housekeeping gene in T cells. You see also that that translates very nicely into a humanized mouse in vivo with progressively higher levels of knockdown moving left to right as we explore some of the well-understood chemical modifications that are so important for siRNA potency. Very nice validation of this idea that an LNP can overcome the specific T cell and immune cell challenges that conjugates have so far been unable to address. When we explore durability across these chemistries, again, with an unoptimized tool molecule for beta-2 microglobulin, you can see that we have very nice persistence of knockdown in a cell model where we have ongoing T cell proliferation in the background. This is exactly the kind of curve for durability that has translated with conjugate delivery to quarterly dosing or more. We expect this will translate here to something like monthly or six-weekly dosing as we further develop it. Very nice combination of both potency and durability. I'll just make the point on this and the prior slide that we're talking about 0.1 milligrams per kilo. Very, very low doses of the LNP. The beauty of siRNA, in addition to leveraging the potency of our delivery system, is that it has a certain catalytic activity. We expect this potency to be a real tailwind for ultimately translating to humans and for development. Zooming out before I conclude, I mentioned earlier that this is a platform that has enormous flexibility. We're starting today on focusing on T cells for development. We already have, in our experience, the ability to swap the ligands on the surface of the stealth LNP, which stays entirely consistent across tissues. We have done a lot of work to develop a similarly selective delivery system for HSCs. We think there are a number of addressable immune cell types for which specific nucleic acid-driven therapies can be developed based on our delivery system. I have tried to give you a sense of why we are excited about targeted siRNA delivery to combat T cell-driven autoimmune diseases. This unique selectivity and reducibility of our delivery system opens targets because we can hit them very, very hard in T cells and spare our other immune cell types. We can do that with the precision and intracellular access that siRNA provides us. We look forward to bringing more data forward later this year and to announcing our lead target and lead program at the mid-year, leading us to be able to build a further platform or foundation of preclinical data through the balance of this year and on the way into GLP development and an IND in the second half of 2026. Thank you for sharing an early part of your morning here, and I'm delighted to take any questions if there are any. Thank you. Yeah. I'm wondering why we decided to focus on siRNA versus all the other possibilities. Yeah, it's a great question. The question is, why did we choose siRNA as opposed to looking at CAR-T or gene editing? I think there's a slightly different answer to each of those parts of your question, so I'll take them in turn. We think messenger RNA is a great cargo. I think it shares many features with si and that it's highly validated and has been used in many clinical contexts. It was actually for that reason that we started a partnership with Moderna about two years ago for the evolution of these T cell-specific ligands. We do expect Moderna will take messenger RNA cargo forward with this delivery system. As you rightly point out, one of the places that could happen would be in the development of in vivo CAR-T, where you get sort of short-term, highly potent expression from mRNA. That is not an area that we're focused on for that reason. That is a division as we stand in the partnership with Moderna. As I was saying earlier, boy, it's a competitive space. There are a lot of different technologies going after that approach. The approach itself to delete B cells is, I think, very promising. On the editing side, our view is that permanently editing T cells is probably less attractive clinically than the kind of reducible and also withdrawable therapy of siRNA for knockdown. As I was saying earlier, there is just a huge potency tailwind with siRNA that we can leverage and multiply against the potency of our delivery. We do not see today that gene editing shares that characteristic yet. Many of the systems really lack adequate potency. Both for clinical adoption development reasons and that potency side, that is why we have steered away from editing at this moment. Great question. Yes. Yes, absolutely. Great question. The question was, say something about the ligands, their format, and can they be adapted or directed at other cell types. One thing we love about this system is that as it relates to the development and optimization of the ligands, it's standing on four decades of monoclonal antibodies technology. We generally have a preference for VHH-domain nanobodies. What that allows us to do is to employ a very rapid target identification development strategy and then to really optimize the specific ligands for development against a given cell type for things like the target receptor density, the rate at which those receptors are internalized, the rate at which they're refreshed or ultimately get downregulated. The bioconjugation technology gives us a lot of flexibility to manage the degree to which we're presenting the ligand far away from the cell surface or close to it or at a level of density that matches the cell target of interest. It is a very flexible platform. It stands on very well-understood development technology. It's quick. We can get to these ligands in about three months. It's cyclable. As you were just pointing out in your question, we have several ligands for T cells. We have several ligands for HSCs. We believe the approach can be applied to erythroid progenitor subsets in the marrow as well as others. Outside of the immune system, we've done it also with hepatocytes. We think other cell types like vascular endothelium and other circulation-accessible cell types can be targeted using this approach. I mean, it stands on the same basis, right? There is a ready supply chain of GMP providers who can produce these ligands, and we're deep into engaging with them already. I think that's time. Thanks again for sharing a few minutes. If you have questions after this, please feel free to grab us in the room or outside. Thank you.