All right, let's start. Saving the best for last. Welcome to the Cantor Global Healthcare Conference. My name is Sarah Medeiros. I'm a biotech associate here at Cantor. With us, we have Climb Bio. I'm really pleased to introduce Aoife Brennan, the President and CEO, Edgar Charles, CMO, and Perrin Wilson, Chief Business Officer. Maybe let's start off with a little bit of an introduction of yourselves and a little bit of a brief description of the company for those not familiar. Maybe we'll start with Perrin. We'll go to Edgar, and then Aoife, we'll let you kind of tie it all up as well with doing the intro with Perrin Wilson. All right, hello, Perrin Wilson, Chief Business Officer. I've been with Climb since early February. My background is a mix of corporate development and strategy, as well as commercial. I've been with both large pharma as well as small biotech over the last 17+ years. Hi, my name is Edgar Charles. I'm CMO at Climb. I've been here for about two and a half months. I come from large pharma, from Bristol-Myers Squibb, where I led programs in autoimmunity development, both early and late stage through commercialization. Before that, I was at Merck. Before that, I was an academic B-cell biologist. Great, and thanks so much for the invite. It's wonderful to be here and to be tying up the conference for you guys. My name is Aoife Brennan. I'm the CEO of Climb Bio. At Climb Bio, we're an R&I-focused company. We focus on developing programs based on validated biology, where we can take products forward that have potential to be best in class in their indication. We have a number of really interesting programs making rapid progress, anchored by our B-cell depleting CD19, which I'm sure we'll get into as the conversation proceeds. We have a second asset that we licensed earlier this year called CLYM116, where we'll have data later this month. We've been very busy. The company has really only existed for 12 months. It had a very interesting foundation story in that it was built in the public markets through a shell company that was called Eliem Therapeutics. It was kind of an interesting formation story. I think we have a lot of work to do in terms of building awareness of who we are and what we're doing. I'm delighted to have the opportunity to share the story and the programs and some of our exciting progress here today. Yeah, I mean, Aoife, Climb is still relatively young. It was, what, June of 2024 that Eliem acquired the private company Tenet. You had that concurrent $120 million private placement. You officially became Climb back in October. Now you're a part of a company with two programs in development. At a high level, how do you describe what sets Climb apart in the immune-mediated disease space? What really attracted investors to come to you guys? Yeah, so there was a lot of recent progress on the biology of B-cell-mediated diseases that really helps us to understand the disease drivers, particularly the potential for a reset. From a patient perspective, I think that's something that has huge potential. That you can administer a therapy and allow patients to have a drug-free remission of their disease is something that could be really powerful for somebody with, you know, generally healthy who's just been diagnosed with this immune dysfunction. Some of the early data around CAR-T was really inspirational, I think, in helping us think differently about some of these diseases that traditionally have required steroids, drugs that come with a lot of long-term toxicity, where the drug is almost as bad as the disease. Some of this early data was really inspirational. I think, you know, at the start of the company, we thought, well, you know, it's inspirational, but also can be limited in terms of its generalizability, just given the complexity of cell therapies and some of the problems with scale and manufacturability and very, very high cost and very, very complex procedures that patients have to go through. The concept was, can we take, you know, some of what we've learned translationally from some of those early clinical studies and think again about using a non-prostitute modality, like a monoclonal antibody, to address similar biology, but do it in a way that's much more scalable so that when we do achieve something, we can deploy it very rapidly into, you know, the millions of patients globally that suffer from these B-cell-mediated diseases. That's the journey that we're on, essentially, and that we've been building over the last year. Yeah, it's amazing. Now, Perrin, I know you guys have two assets in the pipeline now. You have the CD19. You also have an anti-APRIL antibody. These are clinically validated indications for these medical mechanisms. There's just a lot of white space, different high-value indications you guys can go in that where there may be less competition. What does your strategy envision? Are you really prioritizing where to focus your resources and where to expand opportunistically? Absolutely. I think the way we look at it is trying to identify and prioritize indications where there's both a substantial therapeutic potential, but also a substantial commercial potential. For that, that for us means going after indications where there is a high unmet need and where we think our therapies may play a critical role for patients. I think we also think about developability, of course, as a small biotech. We've prioritized indications where there is a clear development path to approval and where there's an opportunity for us to move quickly through development. As you said, there is a lot of white space for both programs. I think indication selection is an area where we spend a lot of strategic time. We'll consider very data-driven decisions as we move both programs forward. Yeah, I mean, let's just dive into it. We'll start with your lead asset, budoprutug. And if I'm saying that incorrectly, I'm just going to say it budo for the rest of this time so I don't embarrass myself. It's your lead asset. It's your anti-CD19 monoclonal. Why CD19 as a target? There are other B-cell depleting agents like CD20, CD38. Edgar, maybe just take us through your rationale here, your thinking behind that. Yeah, great question. We think CD19 is really the optimal target for the B-cell depletion. We view it as the Goldilocks target, given its distribution across B cells. It's expressed throughout the pro-B-cell stage through the mature B cells up to plasmablasts. It doesn't have expression on plasma cells, so you have preservation of the long-lived plasma cell compartment that's responsible for vaccine-related immunity. CD19 has been validated by multiple mechanisms. We see that it has the capability of affecting deep B-cell depletion in the brain and the tissues. This is in contrast to some other antigens of the CD20 and CD38. CD20 has somewhat more limited expression on B cells. Compared to CD19, it's not expressed as early, nor is it expressed as late on plasmablasts. CD38 is limited really to plasma cells with a very high level of expression, a little bit lower expression on early. CD19 has the ability to eradicate the B -cells that are responsible for autoactivity. By B-cell depletion, we can actually stop the disease process upstream, as well as eliminate the autoantibodies in the tissue. Yeah, I mean, Aoife, are there properties of budo that differentiate it from CD19 antibodies, such as Uplizna? Yeah, Uplizna is the first B-cell depleting monoclonal. I think we've learned a lot from their development path. I think it was the product that really established CD19 B-cell depletion as efficacious and safe. They've developed it in rare neurological indications. Molecularly, both products are different. budo has high affinity to CD19, which I think is really important, given that that target is expressed at relatively low levels, particularly as you get into the plasmablast and early plasma cell compartment. We're not fully afucosylated, so we're partially fucosylated, which has some advantages in terms of interaction with FcRn, which is important from a pharmacokinetic perspective. Most recently, we've demonstrated that we can formulate budo for subcutaneous administration. It really is a very well-behaved protein that gives us potential to think about other indications where a subcutaneous formulation may be preferred or may allow us to unlock commercial opportunities that are different from the IV commercial opportunities. One of the advantages just from a development perspective you have in going second is that you can really learn from the innovator, the first product, and think about from a development perspective how, you know, maybe there were learnings around PKPD that you can apply for your program. We've learned a tremendous amount from studying the phase III studies that [Brennan and Cliff] have executed. I think one of the really important learnings that we've had from their study is the importance of B-cell depletion as a biomarker of efficacy. We know, for instance, from their NMOSD study that in the 30% of patients that didn't achieve full B-cell depletion, there was a higher risk of subsequent events. That's something that we can think about in terms of how we're developing our program and think about really making sure we get deep B-cell depletion in all these patients and making sure that we do a really good job of selecting the right dose as we go forward, having learned from that experience clinically. The final piece is just the indication and selection and making sure that we're targeting indications that really make sense from, you know, all of the aspects that Perrin spoke about earlier. I think, in totality, we think that there's a tremendous opportunity for a naked B-cell monoclonal. Certainly, Uplizna has really only kind of scratched the surface and unlocked some of that opportunity. That makes sense. I mean, what about CD19 targeting modalities like CAR-T? How would you compare those? Edgar, I don't know if you want to go first. CAR-T has really shown some extraordinary proof of concept in targeting CD19 B-cell depletion at the tissue level, resulting in durable clinical remission. That's pretty profound. It can be drug-free in some cases. TCEs, T-cell engagers, as we call it, is a drug. I think both have really paved the way for broader B-cell depletion with other modalities such as monoclonal antibodies. Although their efficacy has been very promising with CAR-T and perhaps now with novel elongated emerging data supports that, they suffer from a risk of CRS [and ICANS]. These reactions that are part of CAR-T cellular mechanisms engage large parts of the B-cells by the killing and that cytotoxicity in B-cell engagement. They're responsible for a variety of clinical cellular disabilities. A naked monoclonal antibody approach doesn't have those types of risks. We've seen that practitioners, so physiologists, rheumatologists, in particular neurologists, don't want to have that worry of CRS or ICANS. We see that naked monoclonal approaches may have a broader applicability in the broad swath of patients in the community by explaining those in terms of everything that we care about. A naked monoclonal antibody approach also doesn't have the number one risk of also bicam challenge as far as B-cell, as well as the administration challenge. They require at least a CGI at the end to drive infusion. A naked monoclonal antibody approach has the ability to make IV infusion or subcutaneous administration in the health patient setting. Oh, biomarkers. I know we talked about that a little earlier. Biomarkers are going to increase the importance, especially for accelerating proof of concept. How are you incorporating different biomarker strategies into budo's development, Edgar? Biomarkers are really central to what we do. As Aoife alluded to, we have really the benefit of piggybacking on development programs that have come before us and established and validated a lot of these biomarkers. Central to our hypothesis is that we can affect a deep B-cell depletion. Looking at B-cell reductions, which we know tracks with autoantibody reduction, is going to be really key for us. Certainly looking at autoantibody reductions, and those reductions will be tailored to the disease in question. In the case of pMN, it's PLA2R. In the case of lupus, it includes here, ANA antibodies, et cetera, as well as hard clinical outcomes such as platelet response in immune thrombocytopenia. I think the biomarkers will really give us a very crisp look in a robust fashion, perhaps early on during treatment. We don't need to leverage large numbers of patients to get a good read on how our B-cell reductions are tracking in terms of autoantibody reduction. We anticipate those to translate in a larger patient population. You've categorized your opportunities in the past into three different pillars. We have IgE-mediated diseases, and I think that's basically your lead program in pMN. Single organ autoimmunity or inorganic diseases, and that's your ITP program. Finally, complex systemic diseases, which is your program in SLE. Can you just walk us through your thinking maybe quickly before we dive into these programs? Which one do you see as the major near-term value right now, Aoife? Yeah, yeah, sure. I mean, one of the challenges that we had early on with budo was we had this huge, over 100 B-cell targeted diseases. We had to be careful that we didn't die by indigestion, by trying to do too much and then not learning anything about the program. Once we looked at what kind of rationale, biology-driven framework we could put around kind of trying to make sense of all of this opportunity set, we came up with this kind of three-pillar approach. The first one, the IgG4-mediated disease, is really anchored in the biology. We know that diseases where IgG4 is the isotype of antibody that's driving the pathogenesis behave differently. Like we've known that historically. These diseases, and that's really related to the B-cell biology. We know that B cells that produce an IgG4 isotype are very short-lived. They don't differentiate into long-lived plasma cells. They all express CD19 on their surface. These diseases, just from the biology, are predisposed to respond very well to a B-cell depletion with CD19. Indeed, pMN is a great example of that. We had some early data in pMN showing that we got long-lasting responses in patients. I think those indications have a high technical probability of success, very much rooted in the B-cell biology of the IgG4 isotype of a monoclonal antibody. The second opportunity set with these kind of rare single organ diseases, where often there's a validated endpoint, it's a single registrational study, they're often rare diseases. I think those kind of have a more straightforward development path with often a single pathogenic antibody impacting a single organ system. You know, ITP was a great example of that. Understanding that as a small company and having kind of a very quick-to-market, small-size development program was something that was very attractive. Understanding the role and how competitive CD19 could be in those IgG1- IgG3 single organ diseases was really important in terms of the go-forward development strategy for budo. We were also aware of this large commercial opportunity in the complex rheumatological diseases, where there is a multi-billion dollar opportunity, very validated commercially, but also a lot of complexity based on the fact that these diseases often impact multiple organ systems. There are often multiple pathogenic antibodies involved, but a very high unmet need. Lupus, I think, is a disease that many people are aware of, where it can essentially impact any system in the body. We felt developing a data set that at least would allow us to understand the antibody-mediated B-cell depletion and the potential relative to the data that had been generated with CAR-T and other modalities was really important for us as a company and for the field in general. We had this approach and framework that we thought made sense and where we could execute studies in each one that would really guide the go-forward path on the other side of those programs and help us answer some really important clinical questions. Diving a little bit more into pMN, Edgar, do you want to maybe talk about the current treatment paradigm and where exactly does budo fit in? Budo is still under investigation. I think, you know, currently the treatment with pMN is very supportive in terms of its care. Management of chronic kidney disease, the maximization of the RAS inhibitors, the ACE inhibitors, and angiotensin receptor blockers are important. I think there's certainly room for a true disease-modifying approach. Budo could certainly speak to the leukemic cell therapy and autoantibodies and ultimately improving proteinuria, which is a very clinically meaningful endpoint that directly speaks to the clinic. Do you have anything else to add, Perrin? Yeah, as we think about, you know, pMN, as Edgar pointed out, proteinuria is the key measure that we're looking at from a treatment perspective. There is a substantial opportunity there. There are no approved therapies for pMN, and it's a very significant unmet need in terms of the condition. Patients have a very severe, symptomatic, debilitating disease that manifests as this nephrotic syndrome. You can think about the way physicians approach patients as looking at a third, a third, a third. About a third of the patients will respond to the supportive care type treatments that Edgar mentioned. Two-thirds of patients are really going to continue on and either have very chronic renal disease or they're going to ultimately go to dialysis or transplant. I think as we think about the opportunity for budo and where it fits in, no approved therapies today. Rituximab is effectively the standard of care and used off-label. There are limitations to the CD20 approach, where really you're looking at complete remission of that proteinuria, which Rituximab gets some patients there, about 14% of patients at 12 months, 35% of patients at two years. We think there's a large opportunity for improvement there, and the CD19 biology, we think, can really get at that. You have evaluated it in pI-B to establish a proof of concept in pMN. Can you just walk us through the key elements of the study and the key takeaways from it? Yeah, we did build upon those findings from Rituximab and obviously saw some robust B-cell depletions and proteinuria improvements. We thought we could do better. With budo, we've looked at a small study of moderate to severe pMN patients. It was open-label dose escalation, looking at either 100 mg or 200 mg of budo administered twice, two weeks apart, and then six months later. Enrolled patients had really impressive findings in our review. We enrolled eight patients, five of whom actually received a full course of treatment. The study was actually terminated early by our sponsor just due to business reasons, not due to insane insulin rejections. From those five patients who received a full course of treatment, we saw a complete reduction in B -cells in all five. We also saw a complete or partial response to proteinuria by week 48 in all five. In three of those five patients, or 60%, we saw complete resolution. I think I mentioned the formulation was a very important point. That resolution of proteinuria continued through week 72 of the study. The two patients who continued to evaluate that proteinuria continued to be in remission. We found those results to be quite extraordinary. We also looked at PLA2R antibodies, and we saw a reduction of the individuals who had PLA2R positive at baseline. We saw immunologic remission. The temporality of the results recapitulated the pathophysiology of the disease. We saw B-cell depletion followed by PLA2R reduction followed by proteinuria reduction. That really highly documented the findings. Importantly, the safety and tolerability were really clean. We didn't see any immunity signals. There were no DLTs, certainly no deaths. There were three SAEs that were deemed unrelated to budo by the investigator. We didn't see any AEs related to hypogammaglobulinemia. We actually saw IgG increase, which was quite encouraging to us because we feel that that's actually what led to the. You're moving into phase II, which is expected to initiate the second half of 2025. What lessons from your pI-B can you guide or guided you into the trial design? First and foremost, we had a really encouraging efficacy signal, and we had a very encouraging safety and tolerability signal. That guided us with confidence to move forward into the larger phase II study. It also told us a lot about the split dosing regimen. Dosing in week 1 and week 2, followed by a repeat course six months later, gave us also an understanding of the temporality of the B-cell and the neurologic response that would correlate with what we were agreeing on. It allowed us to know how many patients we really need to see, expecting to see in the next half. I think also it informed our biomarker approach, looking at B-cell depletion and PLA2R. All told, it really gave us confidence for the dose selection. We decided to go forward looking at three doses in dose escalation fashion, followed by an evaluation in week 42. What would you consider a win that would give you confidence into going into a registration of phase III, Aoife? Yeah, so I think what's really important, the endpoint of very long term, as Edgar mentioned, over 42 weeks. I don't necessarily think we need to follow patients for 42 weeks to get the right dose for a phase III study. I think we'll be able to look at some of the biomarkers that Edgar mentioned as being really important in pMN and to guide the dose selection for a phase III study at much earlier time points. I think the one in particular that we would focus on is the PLA2R antibody levels. We know that that's very well correlated with disease outcomes and response to therapy in pMN. In particular, it's not always the case in antibody-mediated diseases. In this disease, the relationship between antibody titer and outcome is very well established. I think looking at that at earlier time points will give us confidence to start moving forward. That's kind of one of the things that we'll be looking for earlier while we're continuing to follow patients for the important endpoint of complete renal response, which may take a little bit longer just based on healing of the podocytes and the lamellar basement membrane. When do you plan on providing data? No, we haven't got into data availability yet for this study. As you indicated, we're initiating that study now and are on track to achieve FPI in the second half of this year. What I can say is, echoing what Aoife has shared, that we consider the endpoints in this study almost like a domino effect of the B-cell depletion happens first. Then you see the effects on the PLA2R antibody, and then ultimately, you can look at the proteinuria down the line. I think suffice to say, you can expect that when we do provide guidance, it will be around the early biomarkers, the B-cell depletion and the PLA2R, which, as both Edgar and Aoife spoke to, will help guide our dose selection and a rapid progression into phase III. I think we'll look to get a few months of enrollment under our belt. Feel really good about the projection we're going to share, but it will be forthcoming. Turning to your second indication, ITP, maybe we'll just go right into the data. You initiated the phase I-B/II-A. How is it designed? Maybe talk about enrollment and what you think of as success for this trial. This is an open-label study. It's a study looking at three different dose levels of budo. Patients are dosed on day 1 and day 14. They have an option for a retreatment between weeks 12 and 36 based upon platelet response. The objectives of the study are PK, TD, safety in the ITP population, and importantly, looking at platelet response. Certainly, depth and durability of B-cell depletion and how that relates to depth of platelet response and durability of platelet response. We're enrolling ITP patients at a platelet count less than 30,000 who have failed a prior treatment. We've started to dose. We're following patients for 48 weeks. We're very hopeful that we're going to see robust B-cell depletions. We're certainly very interested in seeing robust platelet count reductions. This is going to guide further development in all of our IDs. I know you have another indication, which is SLE. In the interest of time, I would love to talk about your anti-APRIL antibody, if that's OK. You plan on developing this in IgA nephropathy, and it makes sense because of Otsuka's anti-APRIL, sibipramumab, which has shown really good efficacy. You do have a different mechanism of action. I just really wanted to understand what you think differentiates your molecule and why you think you have a win. Yeah, I can speak to ultimately for us, it always starts with the patient, right? Working back around, you can talk about molecular differentiation, but if that doesn't translate to something that the patient experiences, then it really kind of stops there. What we really think is going to win in IgA nephropathy is going to be a product that has long-term safety, that gets patients to target in terms of their proteinuria reduction, and that has a low burden of treatment so that patients can take it consistently for a long duration of time. When we looked at our next asset, CLYM116, it was really important for us to evaluate it across all of those components. Some of the data that we'll be sharing later this month will really start to work out what the differentiation story is for this asset. We had this sweeper mechanism of action. It's the only monoclonal in development for APRIL that has this sweeper mechanism, which is a pH-dependent binding of APRIL. It doesn't just inhibit binding to the receptor. It also degrades APRIL as a target. The theoretical hope is that will result in increased efficacy relative to first-gen, but also reduce treatment burden. We do fundamentally believe that the APRIL-only approach is going to be safer over the long term compared to the BAFF/APRILs because we avoid some of the cytopenias that are associated with the BAFF angle, but don't necessarily contribute to the efficacy piece. We think this is a really interesting molecule in IgA nephropathy that can address all of those components that are important to patients. Obviously, a lot of data will need to generate to make that case, starting with some data we'll share later this month that are already dating. This has been really great. If we're sitting here a year from now, what would you like to say has been the key value-creating accomplishments for Climb in the last year? Aoife, I'll let you close us off. Yeah, so I think it's three things. The first thing is execution. You don't do any, you don't get any value creation unless you can execute your clinical studies and your non-clinical development program. The second one is differentiation. We're in a space that's busy with validated targets, so demonstrating how our molecules are differentiated relative to others in the class, I think, is going to be really critical for us. I think the third piece is going to be the indication selection. You know, both assets have a wealth of opportunity, but I think we kind of have to pick and identify, you know, which are the ones that we're going to take forward to generate good medicines for patients and value for shareholders. I think those are the three elements that we're actively working on, and I think we're very confident we'll be able to deliver. Thank you so much for taking the time today to walk us through everything. Great. I'm very excited to see the progress that you have in the next 12 months. Wonderful. Thank you. Thanks, Sarah. No problem. Thank you. With that, I think that's the end of the Cantor Conference. We have the keynote left. Oh, wow.