Morning, everyone. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name is Tom Smith. I'm one of the senior biotech analysts here at Leerink. It's my pleasure to introduce our next company, Climb Bio, and their management team led by President and CEO Aoife Brennan and COO Brett Kaplan. Thank you both for joining us. Aoife, why don't you kick us off here? I know you have some slides to walk through. This will be a little bit of a hybrid presentation. Why don't you go ahead and kick us off, and then we'll move to Q&A. Great. Thanks so much to the Leerink team for having us here. It's always nice to get out of Boston and come to sunny Miami in March. About 15 minutes of a quick overview of the company, and then we'll open up for questions. We are a public company, and these are our forward-looking statements. You can go to our SEC filings for a full description and disclosure of our risk factors. At Climb Bio, we believe that there is a really big unmet need in immune-mediated diseases, which are increasing in prevalence globally. We have come together to address that unmet need and are really driven to become a leader in therapeutic development in this space. We have a focus on immune-mediated disease, particularly on monoclonal antibodies that have broad potential to address multiple different diseases with an underlying pathophysiology. We focus on programs where there's some biological proof of concept, so some human data supporting biological de-risking. We really believe that there is big unmet need and significant commercial opportunity in this space. We're very fortunate to be well-resourced and staffed to deliver on this goal. Our pipeline, as you can see, is really consistent with that overarching strategy. We have two molecules in development. The first one is called budoprutug, which we call Budo for short. It's a B-cell-depleting CD19 monoclonal antibody that we're currently developing in three different indications: membranous nephropathy, ITP, and SLE. I'll tell you a little bit more about those programs later. I won't spend a lot of time on our subcutaneous program, but we have been successful in formulating Budo for subcutaneous administration. We've achieved significant concentration with low viscosity, which really does enable us to think about indications where subcutaneous administration may be very favorable for patients. Earlier this year, we in-licensed our second asset, which is an anti-APRIL monoclonal antibody. I'll tell you a little bit about that asset in a moment. This is the space in B-cell-mediated diseases. The thing that is beautiful about these indications is that at the core, they're really driven by abnormal B-cell behavior, where B-cells are generating monoclonal antibodies that are attacking self. We focused on a number of diseases where we believe there is good tractability, where there's good unmet need. Early data in some of those initial indications can really open up a big potential opportunity in several other diseases that are not currently a focus, but really do provide a lot of downstream optionality for us as we learn more about these assets in development. Initially, to speak about Budo, which is the CD19 monoclonal. This is a cartoon that just demonstrates B-cell development, particularly helps to understand why CD19, I believe, is the optimal target for B-cell-mediated diseases. If you were to design a priori, a target for B-cell diseases, what you would want is something that's expressed on B-cells from the earliest stages of development, but spares the long-lived plasma cell. The long-lived plasma cell is what's accountable for vaccine immunity, for protecting us from recurrent bacterial and viral infections. You really want to preserve that. That's really important from a defense perspective. Being able to target something that's expressed from early B-cell development does give you this big window of opportunity to do something that's durable. Then being expressed up until that plasma cell, plasma blast phase allows you to have rapid onset of effect. This is not just a cartoon. CD19 is now starting to demonstrate in the clinic that we're seeing results in multiple diseases consistent with this expression profile. Unlike CD20, which takes some time to have onset of effect and doesn't really get to those plasma blast cells, CD19 is working in indications where CD20 has failed and in patients who've not responded to CD20 therapy. We believe CD19 is a very exciting target for B-cell-mediated diseases. This is Budo. It has been engineered with very high affinity for CD19, affinity that's higher than anything else in development from a monoclonal antibody perspective. It has this engineering of the Fc component that allows us to interact with NK cells with 100 times greater potency when it comes to destroying those B-cells that have been targeted by the worker part of the molecule. As I mentioned earlier, we have now concentrated the asset to greater than 175 mg/mL with very low viscosity, which allows us to consider development as a subcutaneous formulation. We fundamentally believe that a monoclonal antibody has the best generalizability in terms of unlocking that biology of CD19. The reason for that is that we know how to manufacture these. They fit into a normal supply chain. They can be administered in settings where physicians are used to delivering monoclonals and do not have the baggage of cytokine release and some of the logistical hurdles of cell therapy, for instance. If we can unlock the benefit of CD19 B-cell depletion with a simple naked monoclonal antibody, we believe that could be really transformative for these B-cell-mediated diseases. As we think about the broad potential of the asset, we thought about three different opportunity sets. The first has very high biological tractability and high technical probability of success. That is the IgG4-mediated diseases, which has been led by our indication in PMN, where we already have some clinical data. We are also looking at the single organ autoimmune diseases. For instance, ITP is a great example of that class. Finally, complex systemic diseases, where the biology is a little more complicated, the development is a little more complicated, but the opportunity to do something transformative for patients is really exciting. Initially, to touch on the IgG4 pillar, if you will, PMN is our lead indication in this space. It is a rare antibody-mediated glomerulonephropathy where patients initially develop proteinuria, and then if that is untreated, can go on to develop chronic renal failure. There is no currently approved therapy. Therapies are used off-label in this indication. There really is a big unmet need because of the patients in the US with this indication, about 40%-50% of them are currently undertreated, so need a new therapeutic approach. We have some data. As I mentioned, when we in-licensed this asset, it had an existing clinical data set. There was a study that was done by the prior sponsor, a phase 1b dose escalating study looking at two doses, 100 milligrams and 200 milligrams, in patients who have resistant PMN. The data looked really, really promising. A sequence of two infusions at zero and day 15 and a pair of infusions around six months was able to maintain B-cell suppression throughout the dosing interval and for about six to nine months after that last pair of doses. You can see here the pathogenic antibody is called PLA2R. You can see that it followed a very, very similar trajectory to the B-cell depletion in that in almost all patients, we were able to achieve an immunological remission, which means the pathogenic antibody fell below the limit of detection. Consistent with that, proteinuria, which is the clinical endpoint in this indication, also decreased very much in tandem. We had a complete renal response, which means the proteinuria levels were below 0.3 grams per 24 hours in 60% of patients, which is very, very promising. Just to contrast this with what's seen with rituximab, you get about a 14%-16% CR rate at 12 months following treatment with CD20. This really kind of emphasized that this biology we're seeing around CD19 expression is pulling through clinically, albeit in a small clinical study. I think most importantly, on the safety side, there were no deaths. The adverse event profile is very similar to other monoclonals here, with no real cytokine release to speak of. PMN is our lead indication. We're very excited about taking it forward. We're moving that one forward now into a next study where we hope to continue to generate a very compelling data set. The second kind of pillar, if you will, are the IgG1 to 3 single organ antibody-mediated diseases. Our initial indication in that space is ITP. There are about 80,000 patients in the US with ITP, and a significant proportion of them, about 28,000 patients, are resistant to current standard of care. These are patients who've cycled through multiple currently available therapies but continue to have low platelet count and be at risk of bleeding events. That's the initial target for a new therapeutic development. There's really good biological rationale to believe that CD19 could be transformative in these patients because the current standard of care for patients who have failed multiple prior therapies is to perform a splenectomy. When you take out the spleen in patients who've received CD20 or rituximab, what you can see is that CD20 has actually done quite a good job and that the CD20 positive B-cells indeed have been depleted. What's expanded to take up that niche is CD19 positive CD20 negative cells. Our therapeutic hypothesis is if we can address those CD19 positive CD20 negative cells, we have a good opportunity to really reset the natural history in these patients. We are embarking on a phase 2 study in patients with ITP, where we'll evaluate just that. We'll give them a pair of doses at baseline and then follow for B-cells, antibodies, and return a platelet count towards normal. Finally, in the complex systemic diseases where our lead indication is SLE, SLE is a devastating disease. Despite some recent advancements in therapy, a large proportion of these, generally women, are undertreated and have continued end-organ destruction, which in most cases ends in renal failure when these patients continue and when the antibodies destroy their kidneys. If you look at SLE, there's really interesting data that's been generated from a group in Germany called Georg Schett looking at CD19 CAR-T therapy in these patients. This is probably the best data that's ever been generated in these resistant SLE patients. You can see in the bar chart on the top here that these patients had very high scores of disease activity at baseline. Post-CAR-T treatment, their composite of their, which is called the SLEDAI scores, were back to normal, were basically at zero. CAR-T had really eliminated disease activity in these patients. It was associated with a phenomenon that's being called immune reset, which means that when their B-cells came back, their immune system kind of was reconstituted in a naive way. They didn't get return of their disease activity even after their B-cells came back. This really demonstrates two things, I think. Number one thing is the importance of B-cells in the pathophysiology of this disease. The second thing was potential that these patients can have a long-lasting remission in between treatments. You may not need to necessarily chronically deplete their B-cells. Obviously, CAR-T, while being very interesting from a translational perspective, is limited in terms of its generalizability. It's very cumbersome. These patients have to go through a very challenging regimen to achieve this benefit. We were compelled by the biology here in thinking about B-cell depletion as a potential therapeutic opportunity in these patients. We are setting out to demonstrate that an antibody can perform similarly to CAR-T. This is a study that we are initiating right now in patients with highly active SLE, where we are going to start at a low dose and dose escalate following some of the same biomarkers and clinical endpoints that were performed in the CAR-T studies to evaluate whether we can achieve something similar in these highly active SLE patients. Finally, to touch on our new asset, which is CLYM116, we have been really compelled at our company by the biology of APRIL depletion. Unlike B-cell depletion, APRIL actually modulates plasma cell activity in a reversible way. We really think there is compelling early data, not just in IgA nephropathy, but also reason to believe in other B-cell-mediated diseases, that this could be a really important mechanism. We in-licensed an asset, recognizing that we're behind. There are other assets ahead of us in development. We had a high bar for clinical differentiation. We found this asset that is engineered in two really important ways. The first way is the FC portion of the molecule has a half-life extension technology, which allows us to potentially dose a lot less frequently. The CDR region of the molecule actually has this pH-dependent binding that's been used in other next-gen antibody approaches to really increase the potency and extend the pharmacodynamics. What that does is it allows binding at neutral pH, but then release at acidic pH, which, unlike traditional monoclonal antibodies that can just bind the ligand, this is actually acting like a recycling degrader. I describe it as being like a dump truck. It's taking the ligand, bringing it to the lysosome where it's degraded, and then returning free antibody into the circulation. We thought that was in an area of de-risk biology, had the potential to be a very nicely differentiated clinical asset. This is some of the early data, the non-clinical data on this asset, just demonstrating that we do, in fact, get that pH-dependent binding. That's translating in mouse models to, in fact, this degradation that would be expected based on the MOA. The next step for this asset is to put it head to head with some of the other programs that are ahead in development to see in non-human primates, does it really deliver on this promise of this pH-dependent degradation and binding. As you're all aware, IgA nephropathy is an increasingly relevant disease indication where we believe there's substantial commercial opportunity, particularly in the setting of a lowering of the threshold for clinical diagnosis and kidney biopsy in patients who present with proteinuria, as well as a lowering of the threshold for the clinical target of what patients who've been diagnosed with IgA nephropathy need to achieve to preserve long-term kidney function. We believe this is a great initial indication, but as I mentioned earlier, there's potential for this biology in other B-cell-mediated diseases as well. I'll wrap up with just our outlook and upcoming milestones. This is very much a year of execution for us. We have a number of studies that we're initiating right now, as well as demonstrating that we can advance our Budo subcutaneous program with some non-human primate data later this year. The head-to-head data that I mentioned, comparing 116 to other APRIL binding assets, will be also delivered in the second half of this year. We are very well capitalized to achieve multiple clinical readouts and are very excited to continue to move both assets forward in development. That's it. I'm happy to answer any questions or join you on the couch, whatever works. Yeah, that was great. Yeah, if you want to take a seat, that's cool. Yeah, thanks for the overview. I think most investors are familiar with some of the other CD19 antibodies. We have Amgen's Uplizna that's out there. Maybe if you could just kind of highlight where Budo is differentiated from Uplizna, both in terms of properties of the compound, but also in terms of your development strategy and how you guys have laid out these three different pillars. Yeah, absolutely. Uplizna is a great asset. It was developed by Horizon that was then acquired by Amgen as part of that acquisition. It's approved in a rare neurological indication called NMOSD and has demonstrated successful separation from placebo in a number of other phase 3 studies. It's, I think, really validating for CD19 monoclonal antibody approach based on that efficacy profile. It was probably underappreciated as an asset for a while, but has really come into its own in the last two years. We were really excited to kind of see that validation from those multiple phase 3s, but obviously have a nice differentiation potential for Budo in that we have greater affinity for CD19 in terms of greater potency. We also plan to develop it in a way that allows us to evaluate the full dose range of the antibody, particularly in the context of some of the data demonstrating potential for long-term immune remission in some of these B-cell-mediated diseases. I think from a patient perspective, being able to kind of have this long-term disease-free, drug-free, where you get your immune system basically returns to normal, the disease doesn't come back, is very exciting from a value proposition perspective. Finally, we've achieved the subcutaneous potential, which I think is very important, again, from a patient perspective. Being able to formulate this as something that can be administered subcutaneously is something we're very excited about, not something that has been able to be achieved with any of the prior CD19s. I think it gives us potential to look at diseases that are beyond the scope of the narrow neurological orphan diseases that have been pursued with Uplizna. That's great. Just to highlight, I know we just saw the late-breaking abstracts at AAN where we'll see 52-week data for Uplizna in myasthenia gravis. I think that's a data set we'll certainly be tuned into to see deepening of response and the potential to really achieve, I think, greater durability and depth of response over a greater period of time. Maybe you could just talk about the phase 1 data that you have in membranous nephropathy and some of the B-cell kinetics that you have there. I mean, it looks like some of the patients out to 48 weeks and beyond, you're still seeing depleted B-cells. I guess, what's the expectation in terms of B-cell return and repertoire? Yes, yeah, absolutely. Number one thing I'll say, the Uplizna data, I think, is very exciting. I'm looking forward to seeing the 52-week data because I do think a monoclonal administered every six months will have a substantial advantage over longer durations of follow-up compared to the more short-term data that was announced at AANEM last October. That's something we're following very closely. When you look at some of the clinical data sets with Uplizna, what you see is the patients in the NMOSD study who had greater B-cell depletion actually had better outcomes over the long term. About 70% of patients in the NMOSD study had undetectable B-cells at the end of that first dosing interval. Compared to the 30% where the B-cells were above the limit of detection, those patients who had deep suppression of B-cells actually had substantially lower risk of having a flare of their NMOSD over subsequent follow-up. I think that data set really emphasized, it was the first inkling that we got that really suppressing the B-cells could be very important from a long-term efficacy perspective. If you look at the CAR-T data, what you can see is the patients who have the best B-cell suppression actually have the best outcomes. There is this dynamic between deep B-cell suppression and clinical outcomes over time that I think we've seen now across two different modalities, one being a monoclonal and the other being a cell therapy. That's an amazing advantage to somebody like us coming along behind because it means we kind of now know that this biomarker is going to be really important and that we need to find the dose early in development that's going to give us the best potential benefit from the asset as we go into phase 3 studies. That's been something we've been following very carefully. I would love to see it as part of the AAN presentation, a correlation between B-cell suppression and maybe some of the clinical endpoints. I do think they'll have enough N to be able to kind of parse it that way. If anyone knows Jay Bradner, please extend my request for some of those data. Ask him to be so kind as to show us some of the data. I do suspect, based on what's known to date, that that relationship will continue to pull through across all different indications and studies. I think that gives us an amazing opportunity to make sure before we initiate those phase 3 studies that we really have found the right dose that's going to get everyone to where they need to be from a biomarker perspective. Yeah, that makes sense. If you could talk a little bit about your plans in membranous nephropathy. You've talked about advancing it to late phase development. I guess, what are the current thoughts on what the next steps look like and what are the gating factors to kicking off that next study? Absolutely. As I mentioned earlier, dose, dose, dose is important. We had this data set from two doses, 100 and 200. The study was discontinued prematurely. I wish we had more data across the dose range. We had eight patients, of whom five actually had follow-up data. In those patients, you see a very nice clinical efficacy, but we think we can probably do more because, as you saw from the B-cell graphic, not everyone got to that target B-cell number throughout. There were two patients where we did not get full B-cell suppression. Sure enough, they were the patients who did not really get to that clinical complete response. We really need to make sure that we have the right dose. The next study is likely to be something that kind of allows us to expand that dose range to get everyone where they need to be. The beautiful thing about PMN is that we know what the clinical endpoint is. It is the proportion of patients that get to that complete response. Once we have the dose and we have our manufacturing and chronic tox in line, getting to that phase 3 design, I think, is going to be relatively straightforward. That is the plan this year. We are making great progress on that and continue to be very excited about the opportunity in PMN. That is great. For the ITP program, you have kind of designed this as an open-label study. I imagine as you enroll patients, you will have some visibility as we go. I guess, how should we think about timing and cadence of data from that study? I know it is early. We have not stood it up yet, but do we think that this is potentially like a 2026 early look at data? What would you be looking for from that study? Yeah, ITP is, from a development perspective, nice because you have the platelet count as your kind of objective endpoint. In these chronic and persistent ITP patients, the placebo response is almost zero across multiple phase 3 studies. Unlike diseases like SLE, where you're dealing with composites or patient rating or physician rating scales where there can be a lot of variability, you have this nice kind of objective biomarker that is the clinical approved endpoint that's also very important from a clinical relevance perspective. I think there's a lot of advantages to ITP. It's really about the number of patients that get you a stable estimate of the% response. There's a range in terms of the number of% responders in this population. The FcRns are pursuing development here too. The response rate there is being about 20%, kind of somewhere between the high teens, low 20s. I think if we can demonstrate a stable rate in the appropriate number of patients, I think that's going to be really meaningful for both this modality in terms of the mechanism of action of demonstrating CD19 in this kind of area of high unmet need, as well as for Budo's potential future development in ITP as an indication. Yeah, okay. That makes sense. We're going kind of rapid fire through each of the three pillars here, but let's talk quickly about SLE. This is, I think, increasingly competitive space. I think we have over 70 phase 2 or phase 3 programs that are out there either actively enrolling or active. I guess just how are you thinking about Budo in the broader competitive landscape? As you're trying to enroll your lupus program, how are you guys thinking about targeting patients and sites and getting patients enrolled there? Yeah, there was a beautiful graphic that I saw recently. I don't think it was from you guys, but someone had put together the mechanisms in SLE and then the efficacy in terms of the SLEDAI-4 rating. What you can see from that across all the mechanisms, the B-cell targeted therapies really stand out in terms of being able to move the needle. There are a number of assets that have demonstrated positive phase 2B data in this indication, but the delta from placebo is kind of high teens, 20s. You're still leaving a huge proportion of patients there with continued uncontrolled disease. When you look at the B-cell targeted therapies, it's a sliding scale. The more you impact the B-cells, the higher the SLEDAI-4 scores get. It is a really great graphic representation of both T-cell, interferon gamma, the various modalities, as well as the kind of delta. The higher the impact on B-cells, the better the response you get. I think it has really given us a lot of—it has forced us forward in SLE despite the difficulties of enrolling this study because we really do think that there is this kind of sweet spot. CAR-T works, the data is beautiful, but it is not going to be broadly applicable to patients with SLE globally. It is a relatively common disease. We really want something that is going to be able to treat all patients regardless of where they are. A CD19 targeted monoclonal antibody can get up to that kind of high end of the range in terms of the efficacy on the SLEDAI-4, could be a real game changer in this indication. Despite the difficulty, we really feel compelled to evaluate Budo. It's not an area where Uplizna has evaluated. We think getting a higher dose and really doing the right study in this indication could be very important. It's a substantial commercial opportunity. If we can crack that nut, it could be a huge opportunity for us and for Budo and for patients. I think the biology is very compelling, and we're committed to moving forward. Yeah, that's great. I know this is an in-licensed program for you. Just remind us on the IP and exclusivity and I guess whatever strategies you're undertaking there to extend the exclusivity. Yeah, sure. It's an asset that was actually developed by Merck KGaA. We have good IP coverage and are pursuing a number of different strategies that will continue to extend the IP there. Ultimately, exclusivity from a regulatory perspective will also be applicable here. We're confident that we'll be able to continue to protect our innovation over the normal kind of span that you would expect from a monoclonal. Got it. Just quickly on 116, looking forward to the preclinical data later this year. It sounds like we're going to see this kind of head-to-head versus a lot of the other APRIL targeted compounds that are out there. What's sort of the next steps after that preclinical data? How quickly could we get this into the clinic? Yeah, we're in IND enabling studies right now. That head-to-head study is now gating our preparations for IND. If it continues to look like a compelling opportunity based on the external piece as well as the internal data that we generated, we're prepared to move into clinical studies, probably a healthy volunteer study very, very rapidly. More to come on that later this year as we solidify our timelines and our goals. Got it. We'll stay tuned on that. Last question, just in terms of you in-licensed 116, you talked about sort of the cash runway. I guess maybe just speak to the appetite for additional business development and I guess what's contemplated in that runway. Yeah, for now, we're in digestion mode. We have two really compelling assets that we absolutely need to execute on. That's our focus certainly for the next couple of months. We do have, we're building capabilities around development. We're building expertise in B-cell targeted diseases. We're constantly on the lookout for something that could be interesting and compelling, but have a very high bar for something that's clinically differentiated in the space. Got it. That makes sense. All right. We're up against time, but I'd like to thank Eva for joining us. We'll stay tuned for the Climb Bio story. Great. Thanks so much. Thank you.