Happy to have Climb Bio here for our next fireside chat, CEO Aoife Brennan and CBO Perinn Wilson. Maybe kick it over to Aoife to start things off with a quick overview of the company, and then we'll get into a Q&A. So Aoife, over to you.
Great. Thanks so much, Alex, and thanks to the Steve team for having us back again for the I&I conference. So Climb Bio is a relatively new company. We're just celebrating one year since we relaunched the company as Climb from Eliem. We're a company that focuses on developing monoclonal antibodies for I&I indications. We believe that there's a tremendous opportunity with large commercial indications, but also a lot of unmet needs in areas where the biology is relatively de-risked, where we can develop a well-validated platform like monoclonal antibodies to address that unmet need. We have two programs led by Budo, which is a B-cell depleting CD19 monoclonal, and then a second asset that's moving towards the clinic called CLYM116. That's an APRIL- targeted monoclonal. And I know we'll get into both assets as we go through the Q&A today. So that's the company in a nutshell.
Great. So maybe starting off with Budoprutug and the CD19 space, I guess, you know, for investors who are focused on CAR T and T-cell engagers within this category, what are folks missing about what antibodies can do, really?
Yeah. So we think about the B-cell space. Number one is, there's a tremendous number of diseases where B-cell biology is really the driver of the pathophysiology, and for a long time, we had to convince people that CD19 was the best target to pursue among all of the B-cell targets that are available or that are expressed on the surface of B-cells, so I think what we're seeing now is a lot of interest in CD19, and we fundamentally believe that if you just look at CD19 and all the various modalities that you can use to go after CD19 positive B-cells, that actually a monoclonal antibody has not really been exploited to the extent that it can be exploited to address the unmet need in B-cell targeted, in B-cell mediated diseases.
And the reason that a monoclonal, I think, is still in its very early innings in terms of addressing that unmet need is that we know monoclonals can be manufactured at scale. They can be delivered safely. They can be delivered in community healthcare settings. They can be delivered IV or subcu, right? They leverage NK cell-based cell killing, which is not associated with cytokine release. And I think physicians are comfortable with that profile. They're using these therapies in their clinical practice. They're using rituximab to treat patients currently. So I think when you think about that profile and think about how many patients can potentially benefit, I think making sure that you're fully exploiting that modality before kind of thinking about going up the chain of complexity just makes a lot of sense to us.
Thinking along that spectrum of benefit-risk to those indications where maybe the benefit-risk profile of a CD19-targeted monoclonal makes a lot of sense for patients and for physicians, but we saw a large opportunity. It's not to say that there aren't opportunities for other modalities like T-cell engagers and CAR Ts. There probably is space for more than one modality in this huge space of B-cell mediated diseases. But we think that there is a lot of opportunity for a monoclonal antibody modality in CD19-targeted diseases. And as only the second CD19-targeted depleter to go into I&I, the first being Uplizna, we think Budo is a very exciting asset. And we're making rapid progress in generating data sets in diseases where a CD19 hasn't been evaluated before. So it's a very exciting space.
Yeah. I want to get into differences versus inebilizumab specifically. But before we do that, you have this conversation about T-cell engagers and CAR T, and people think about CD19 depletion with an antibody as the comparator there. Is that the right comparator? What does the product profile look like that you're solving for? Should we be thinking about comparison to other B-cell modalities like FcRn or things like that when you think about budoprutug?
It's kind of funny because sometimes I think as investors, you think that we're playing a zero-sum game, right? With each indication or with each modality, there can only be one winner and that you're forced to choose the single modality within the CD19 space or the single modality within the Myasthenia Gravis target space. And in reality, that's not the way a lot of these markets play out, right? And that's certainly not the way physicians make decisions, and that's not the way patients make decisions. I think it's all about what's the right clinical profile for that given patient and that given segment within that given disease indication. And I think it's about thinking from the perspective of the patient and the physician, how they make decisions, right, and how markets grow over time as better treatments become available for these patients.
And I think understanding that as your programs go through development and how you unlock some of those opportunities, I think is really critical for all of us in the drug development space. Because if you're not doing that and developing things in a smart way, then it's very difficult to deliver value for patients and to deliver value for shareholders, regardless of how sexy your modality is, right? You could be doing the Nobel Prize-winning science, but ultimately, if you're not delivering for patients and for prescribers, you're not actually going to do anything for investors either. So I think that's how we see the CD19 space and the monoclonal antibodies. It's not a us versus them. It's really been laser-focused on the unmet need in each individual indication and where does a monoclonal antibody fit.
And then making sure you're staying laser-focused on that and not worrying about what's left or right of you, but just really staying laser-focused on how do you and what's the quickest path to getting to those patients in need. And that's certainly the philosophy that we're taking into this.
So then why aren't there more CD19 antibodies in the clinic right now for autoimmune disease? Why is it really just you and Uplizna?
It was kind of, I think, CD19 was a late bloomer. It was kind of like one of these targets where all their friends were dating in high school, and it was left behind. Like CD20 was the captain of the football team, and CD19 was kind of the geeky chess club kid who didn't really bloom late. But I'm kind of all joking aside, CD20 kind of moved rapidly ahead from a scientific perspective when you just look at how many drugs have been developed targeting CD20. And the reason for that, I think, is historically CD20 kind of became prominent because of the oncology work, right? And that makes sense. It is a narrower expression profile in terms of B-cell development when you look at the graphics around B- cell lineage, but it's expressed with much higher density on those cells.
When you're thinking about oncology where you have a rapidly dividing clone and you really want to hit something very hard so that you can rapidly deplete those cells and bring down the cell population, that makes a lot of sense, right? In oncology where rituximab was developed initially, and then multiple other drugs followed on from there with slightly different profiles, subcutaneous, different potencies, it was all about CD20 for a long time. We kind of forgot about CD19. Honestly, it was kind of like there were a couple of drugs developed that were forgotten about and not a lot of value was attributed to them. They kind of moved slowly in development until someone kind of started to think about them.
And fairly, a lot of credit is due to those innovators, right, who started to think, well, maybe we should think differently about these targets in immunology. So rituximab started to be used in immunology indications. Initially, it was like, oh, you can't do that. It's an oncology drug, dangerous, depleting B-cells in patients with I&I. You can really only use it in very severe immunology indications. Well, it turns out that it wasn't really all that dangerous. And the risk of infection that everyone was very concerned about wasn't really manifest. Patients could. You could deplete someone's B-cells with CD20, and the sky didn't fall in. And it was actually OK. And immunology started to get a little bit more comfortable with the concept of B-cell depletion in immunology. And then I think we started to look at CD19.
And so while the biology of CD19 was known for a long time, there were some companies that had these CD19 assets. And the CD19 that Horizon had was one that was being developed in NMOSD. They couldn't get a lot of interest in that asset, but actually had stunning efficacy when that NMOSD study was unblinded and now has demonstrated efficacy in multiple different indications, including Myasthenia Gravis and others. So it was kind of like a latecomer to attention. And I think that's because the biology there, CD19 is expressed in a broader subset of B-cells, right? It starts being expressed earlier. It's expressed in plasmablasts and some of the peripheral circulating plasma cells. And where you don't have to rapidly kill cells, where you actually have time, that kind of broader expression is more important than the relative expression profile.
So I think we're starting to see some of the biology play out. And it just took us a long time to understand, similar to GLP-1, we've known GLP-1 biology for a long time. The original papers were published many years ago, but it hasn't been exploited from a drug development perspective until relatively recently. I think you're seeing a similar story with CD19, and it's starting to kind of come into its own now in terms of immunology indications.
So then drilling down a little bit more, what are the key differences between Budoprutug and [anabolism AB] as the main comparator?
Yeah. So there are molecular differences that I think, frankly, as we move forward in development, will become relatively less important. But from a molecular perspective, we have higher affinity for CD19, and we're partially afucosylated. So Uplizna is fully afucosylated mAb. Budo is partially afucosylated. The afucosylation is what determines the ADCC potency, and that's what increases the affinity for the Fc receptors on NK cells. And then importantly, we've been able to formulate Budo for subcutaneous administration, and we do not have CDC, which potentially has the potential to have less IRRs as the product is administered. So I think they're kind of some of the molecular components that are different between both products. And then I think as we think about taking it forward in development, we have the opportunity to think about different dosing strategies based on how the science has evolved.
We now know that B-cell depletion is really important to maximize efficacy. And we also know that there are different patient populations and diseases. And we can think about, are there patient populations where we can achieve immune reset or give them a long duration of disease-free remission? So a lot of these things and learnings from other modalities and from some of the Uplizna studies we're taking into account as we move forward in development. So I think we'll be able to think about how we position the molecule in different ways compared to how Uplizna has been developed.
Yeah, and I wanted to touch on your indication selection here because obviously there's a lot that you could go after, and you've chosen the initial three with Membranous Nephropathy, ITP, and SLE. You want to walk through at least at a high-level kind of the choice of those three and why they make sense?
Sure. Maybe, Alex, to start out just on an overall indication level, the way we look at things is there are a lot of different directions you can go with CD19. I think the biology lends you the opportunity to pursue multiple indications. First, we want to ensure that there's a significant therapeutic potential there, but then also a significant commercial opportunity. And there, I think our bar is really looking at the unmet need that we could address in each of those indications. Because if you're addressing that unmet need, meeting those TPPs, I think that commercial opportunity comes. And then the other lens we look through is from a regulatory perspective, ensuring there's established regulatory pathways, clear endpoints for approval. And I think that helps us de-risk our development overall. And so those are two of the factors.
And then I think of all the indications, we've provided a framework for ourselves to think through it. And we separate the indications into really three strategic buckets. The first bucket is those IgG4-mediated diseases where there's a clear pathophysiology for targeting B-cell depletion through CD19. And I think some of the examples there are the myasthenia gravis, which Aoife mentioned with Uplizna. And in that bucket, our lead indication is PMN, primary membranous Nephropathy. And we've just initiated a phase two study in that indication, and that study is now enrolling. And that second bucket of indications is those single organ orphan diseases where there is clear biology for targeting B-cell depletion and even targeting CD19. In that bucket, an example is NMOSD, where it really affects a single organ system, and CD19 has demonstrated clear efficacy there.
The indication that we elevated within this bucket is ITP, hematologic indication, and we've initiated a phase I b/2a study there. If we move over to the third bucket, if we think sort of along the risk spectrum, we have the complex systemic disorders. These are really those autoimmune diseases that are affecting multiple organs throughout the body. There's a very heterogeneous patient population and more of a development challenge as we think about going after these indications, but also clear validation for CD19, and that's through other modalities. We've started to see some data from the CAR-Ts and some of these indications. Really here, we've elevated SLE. We have an ongoing phase Ib study in SL now underway.
Great. And then maybe just can you talk about how these trials are ongoing and the expectations for cadence and data updates?
Yeah, sure. Do you want to talk about that? Yeah. So I think all of those studies are now underway. We also have a phase I healthy volunteer study for the subcu formulation of budoprutug, which is underway. So we're actively enrolling in all four of our studies. And in terms of data, the first piece of guidance we gave back in August was with the subQ study. We expect data in the first half of 2026. And with the ITP and SLE studies, we've guided to providing timing for data availability later this year. And with PMN, we're just getting that study underway. So I think we'll provide further updates on data availability and timing to guidance as we progress and start to get a couple quarters of enrollment under our belt.
Yeah, and then I think, Aoife, you alluded to this idea of how will dosing ultimately evolve here? I guess, what will we learn from your initial proof of concept studies to get at least some answer to those sorts of questions?
Yeah. I think we're still learning a lot about B-cell biology vis-à-vis some of these indications. What is clear is that it's all about the B-cells, right? And getting the B-cells depleted is related to the subsequent response that patients have. And if you look across all modalities, I think there's a clear relationship there. So we want to make sure that we have a unique opportunity coming second, and we want to make sure that we're selecting the right dose and that we're not just choosing the dose that gets the peripheral B-cell count down because there is potential that a dose higher may actually be important as it comes to the tissue-resident B-cells.
So it's not just about stopping when we see the peripheral B-cell count going below the lower limit of detection, but actually continuing to dose escalate until you're seeing that the B-cells that come back are actually that naive phenotype. And that, unfortunately, requires a little bit of patience because the B-cells take a few months to come back. So you have to wait until you dose a patient and then wait not just until the B-cells disappear, but until you start to see them come back. Because there is a risk here that by moving too quickly, that you actually choose prematurely a dose that may be suboptimal. So that's what we've guided to in terms of the dose escalation.
We've managed to convince regulators that doing a dose escalation beyond what may be necessary to deplete peripheral B-cells is maybe important here based on what we've learned from the biology. And so all of our studies, you'll see, are dose escalation studies with small, medium, and large dose to really look at that hypothesis, which I think is going to be important. Because if we can give patients a disease-free remission where their B-cells can return and the disease and the pathogenic drivers do not come back, I think that could be something really important. And to be able to do that with the safety profile of a monoclonal could be really transformational.
So I think we want to make sure that we don't foreclose that opportunity by moving too rapidly with a suboptimal dose, particularly given that we have safety experience from oncology up to a gram weekly over four weeks, right? So there's no safety limitation. If we had cytokine response for some other reason that was limiting us, fine, but we don't have that limitation. So I think we have to make sure we do a good job on that side of things. And that was a real driver in some of our decision-making around these early studies.
So maybe in the last five minutes or so, let's talk about 116. I guess there's a lot that you can do with CD19. What's the reason for adding another program to your pipeline, and how does APRIL fit into the broader strategy here?
Yeah. So when we looked at CD19, we wanted to be very focused. It's all about the B-cells here. But we recognized that there was one component to the B-cell repertoire that we didn't address, which was plasma cells. And when we looked at the various plasma cell targets, the two that we really liked were APRIL and BAFF APRIL. We thought that those had the nice profile from a benefit-risk perspective. But we also realized that there was a high bar from a differentiation perspective. So we set out to look and see were there assets that could beat sibeprenlimab on the APRIL side or could beat povetacicept on the BAFF APRIL side. If there were no assets, we were going to walk away, right? We weren't going to do anything.
But we asked the question, if there was an asset that was complementary that had a potential to be differentiated from either of those kind of standard setters, if you will, we were interested in moving forward. And we found an asset that we thought had a very interesting but early story. It was very early. There was very little data, but we had a great partner, and we were able to put together a deal that really made sense for us. And so when we saw an opportunity, it was very much we had built a team to do monoclonal antibodies in B-cell-mediated diseases. So it really made sense, and we were able to do the transaction without shortening our runway.
So as a business person, there's very few times that you could get to check all of those boxes, and we thought that it made sense to do so. So we're very excited about the asset. We think we've been able to create tremendous value, and we'll be unveiling some of the data in a couple of weeks here and kind of showing the drivers behind the decision. And we're excited to move forward.
Yeah. Without spoiling your R&D day, you have shared some elements of the profile that highlight some of the elements of differentiation versus sibeprenlimab. Can you just sort of walk through a few of those?
Yeah, sure. So we think sibeprenlimab is a great drug, but we think APRIL is the way to go. In IgA Nephropathy, we think IgA Nephropathy is a big market. And the differentiation is really going to be about making sure we have maximal APRIL suppression and that we're doing it in a way that has the least possible burden for patients. And when you look at other disease areas like complement and how that space has evolved over time as new kind of next-gen products have come about, it's been all about the antibody technologies that have been applied to really address that unmet need. And we found this molecule that employs sweeper technology, which means it's a degrader of APRIL, as well as having half-life extension technology. It was early at the time. We didn't know how that would apply to the APRIL space as a soluble target.
We've generated some data that gives us kind of some hints into how that might translate to humans. So it was kind of differentiated in that way as the only sweeper that we are aware of that has been developed against the APRIL target. So we were excited by that early science being kind of antibody drug developers. And so we'll be excited to kind of continue to demonstrate that this can do something interesting in the APRIL space.
Yeah. Okay. And so R&D day on the 29th. And then maybe in the last minute or two here, can you talk about your cash runway and what's included in those assumptions?
Sure. So our current cash runway is through 2027. And that really allows us to prosecute all of the clinical studies that we've laid out and provide data from all of those studies and also advance the 116 program into the clinic.
Great. Well, appreciate you both taking the time. Always a pleasure.
Awesome. It's great to chat. Thanks.