Second annual Autoimmune and Inflammatory Disease Virtual Conference focused on skin diseases. My name is Emily Bodnar, and I'm an Equity research Analyst at H.C. Wainwright. I'm pleased to introduce Ronald Martell, who is the Chief Executive Officer of Jasper. Ronald, for those who are a bit newer to the story, could you provide us with a brief overview of Jasper, your pipeline, and some of your recent milestones in the past 12 months? Certainly. First, Emily, thank you to you and H.C. Wainwright on behalf of all my colleagues here at Jasper. It's a pleasure to be here meeting with you today. So yes, Jasper, 2023 was quite an eventful year for us, and we're off to a great start for 2024. In 2023, we announced that we would be filing INDs and CTAs in both CSU and CIndU with an objective to achieve first patient in the CSU study before the end of last year, and we achieved those objectives. And also stated objective for initiating enrollment in our CIndU study in Q1 of this year, and we announced a couple of weeks ago that we've enrolled the first patient in that study. We also provided an update on enrollment in our CSU study a couple of weeks ago as part of our first quarter or our end-of-year earnings. We stated that we're enrolling the second cohort in that study. So, 2024 will be quite a transformational year for Jasper. As we've guided, that we'll have the initial data from our chronic spontaneous study, the BEACON study, that we'll have that data in Q3 of this year. Awesome. Your lead asset briquilimab targets c-Kit, and as you mentioned, you're evaluating it in CSU and CIndU. What role does c-Kit play in the immune system, and how might it be effective for some of these diseases? Yeah, I think, importantly, you know, it all starts with the biology, and here at Jasper, we take great pride in following the biology of any of the diseases that we're approaching. And that's a great question, Emily, and it's really important to understand mast cells, specifically in CSU and CIndU, and in a variety of other immunologic diseases that present with mast cells that are either mast cell-mediated or mast cell-driven. And c-Kit is known to be a primary survival pathway for mast cells. If you block c-Kit on the surface of a mast cell, and if you block it to a significant enough threshold of concentration, then you will shut down all signaling to that cell. And internally in the cell, by blocking the external signaling, by inhibiting the normal ligand from being able to bind, you shut down FOXO3a inside the cell, and FOXO3a mediates Bim. And when you shut that down, then Bim is upregulated, initiating apoptosis, and it's an irreversible apoptosis that happens within hours, and that's an important survival mechanism for the cell. And what we know is that that's the primary mechanism by which we can then deplete mast cells. Kind of going along with that topic, you recently presented preclinical data showing that c-Kit plays a role in anaphylaxis and allergic reactions. How did some of that preclinical data inform or add to what we've already known about c-Kit's involvement in mast cell function? And did that kind of help with any sort of strategic development for your ongoing studies? Yes. That was a really key study for us to perform. And first, I think it's important to talk about the Jasper Mouse. So, in the mouse model, and typically, that's why you won't see any real animal studies that are conducted, is the mouse external domain of c-Kit does not bind to a human antibody. So we've engineered a mouse where we've knocked in the external domain of the human c-Kit, so that it can bind, and we can test directly in those animal models, briquilimab or other antibodies to c-Kit. So we have an incredible resource that enabled us to test whether it's in this anaphylaxis model or other disease models, and I'm certain we'll have an opportunity to talk about that. But based on having that Jasper Mouse, we were able to test in an IgE-mediated model. We know that IgE induces anaphylaxis, and what we're able to demonstrate in this study is by using briquilimab, not only did briquilimab not raft IgE, but it also prevented the degranulation of the mast cell by blocking c-Kit. So c-Kit plays an important role in mediating anaphylaxis, and specifically using briquilimab to block c-Kit inhibited anaphylaxis, IgE-mediated anaphylaxis from taking place in these animals. ... c-Kit has also gained clinical validation as a target for CSU with an asset called barzolvolimab. Can you walk us through some of the data that's been presented with that asset, and ways that your asset briquilimab differs? Sure. So, Celldex and barzolvolimab have certainly taught us a lot. This is, I think, one of the great times to be a fast follower here, because they've taught us a lot in this space. What they've taught the space is that, by blocking c-Kit, as was the hypothesis, that you could deplete mast cells and safely deplete mast cells. So that certainly has been validated. It's long been known that c-Kit is a validated target. We now know that we have an antibody that can drug that target, and now with Celldex's data, the clinical relevance of drugging that target is understood. The other thing that Celldex has really taught us, also about the biology of the mast cell, is that when you deplete mast cells, so you initiate that irreversible apoptosis, that happens within hours. Within days or weeks then, a large portion, if not all of the mast cells in the skin, are dead and leave the skin. But importantly, what they've also taught us is that mast cells don't return to the skin until maybe week 18 or later. So they're depleted for a long period of time, and the underlying biology of that has been understood for some time as well, that mast cells are a very long-lived cell in the body. All of us have mast cells in our skin that we were probably born with. So the body doesn't need to produce many mast cells. When you deplete a mast cell, they come from the bone marrow. A progenitor is produced and put into circulation, it implants in the skin, then it has to mature in the skin, and that takes a long, energy-expensive time for the body to do that. And so, that's really informed our thesis here on optimal biologic dosing, and where we think it's, it's really critical here to understand that the, the biology of the mast cell is, is driven by c-Kit for survival. You block that, the mast cells will die and leave the skin, and then takes a long time for the, the mast cells to come back. We think that combined with some of the attributes and differences in the antibodies, so both antibodies are IgG1 aglycosylated humanized antibodies. The similarities really stop there, though. Our antibody, in order to aglycosylate or nullify the Fc, it made a single change at N297, and it's arginine to a glutamine. So a single change in the structure of the antibody to nullify that Fc. It's really important, as you were one of your earlier questions about anaphylaxis, it's really important to not be able to bind complement or activate ADCC in the presence of a mast cell. So that's really important. But we also know that barzolvolimab has made about six structural changes to their antibody, both to nullify the Fc, as well as to lengthen the half-life. We know in the antibody community, the more structural changes you make to an antibody, the higher probability you have of ADAs. To date, we've seen about 15% ADAs with briquilimab, and the only data we've observed so far have been stated from Celldex a year ago, I believe, at AAAAI, where they stated they had about a 51% ADA rate with their IV formulation. So we'll keep an eye on that moving forward. What we know about briquilimab to date is that the ADAs we've observed have not affected the PK or the PD of the drug. And the last difference here that I'll speak to for the moment is the difference in half-life. So our half-life is about nine days. barzolvolimab is about 21 or 22 days. And so, again, back to the concept of optimal biologic dosing, that we believe that, it's important to, have enough drug on board to deplete the mast cells, but then give the patient as long of a drug-free interval as possible before you need to re-administer the drug, when the mast cells start to come back, which appears maybe in that 18 or longer week period of time, and that's what we're evaluating in our BEACON study. Going along more on that topic, you presented phase I healthy volunteer data, which showed mast cell depletion from a single dose. Maybe just summarize the safety profile that you observed in the phase I study, and what dosing strategies you're now using in the BEACON study? Sure. So in the healthy volunteer study, we evaluated 77 healthy volunteers that participated in that study. We used four dose cohorts, 42 mg, 84 mg, 158 mg, and 280 mg that were used to dose in this study. And what we observed was at the 42 mg dose, there was only one healthy volunteer that experienced significant mast cell depletion. And again, that supports the thesis of a threshold of concentration, that below the threshold to initiate apoptosis, you get signal inhibition, you'll see a drop in tryptase, but you don't see the mast cells deplete from the skin. You're not activating apoptosis. With briquilimab, we believe that that threshold is crossed at about 0.8 or 1, which corresponds to the 80 milligram dose that we'll be using in our clinical trial. In that study, when at the 84 milligram, we saw about 65% of the patients have complete mast cell depletion. And we saw a nice dose response curve as we increased dose in those other three cohorts. And so it was validation that you need a threshold of concentration to deplete mast cells to initiate the apoptosis, and then with increasing doses, you get deeper mast cell depletion. On the safety side, we observed in the healthy volunteers a very acceptable safety profile. So we didn't see significant impact on the hematopoietic endpoints that were observed in the study, say a drop in neutrophils or other indices on the hematopoietic side. We only saw the graying or dysgeusia or effect on the taste buds at the 280 mg dose level. So we again believe that you know these things are c-Kit driven and exposure driven. And so if we can avoid those really high doses and can only have the drug on board when it's needed to deplete mast cells, it might provide us with the opportunity to avoid some of these on-target c-Kit adverse events. Okay, great. And you mentioned you plan to have initial data from the CSU study in the second half of this year. So how would you characterize positive results based on clinical data we've seen in this space so far? So in our study, we're evaluating a number of different dose levels to initiate the apoptosis and deplete mast cells, and we're also looking at extended dose intervals. We are looking at the lower doses at four-week intervals, and as we increase the doses, we're looking at eight weeks and 12 weeks. And at the upper dose, we're looking at a single dose without a repeat dose. So coming out of this study, we should be able to understand what's the optimal dose to deplete the mast cells, and then what's the longest interval of time that we can go before we give a repeat dose. And we would expect from that initial data to be able to... We're using the same endpoint that Celldex has used, the UAS7 at 12 weeks, and we'll report that out on the 80 milligram and the 120 milligram dose levels with a Q8-week dosing. So when we report that initial data in Q3 of this year, even though we're not supposed to do it, we all do it, we'll be able to put these studies side by side and look at the UAS7 at 12 weeks compared to barzolvolimab. And we think a win would be anything that, you know, from an efficacy standpoint, that's comparable to Celldex. Okay, great. Kind of shifting to the CIndU side, how does that indication differ from CSU, and what kind of evidence do we have that it could be- that c-Kit could be an effective target for both of these types of urticarias? But both diseases are mast cell driven. The perpetrating cell in this disease is mast cells, or are mast cells. And again, Celldex here has paved the way for us, demonstrating that by blocking c-Kit, you drop tryptase, you deplete the mast cells in the skin, and you have complete responses in these patients. In our SPOTLIGHT study, in the CIndU study, we are evaluating two patient populations with CIndU, symptomatic dermographism and cold urticaria. They make up about 70%-80% of the CIndU patient population. The design of this study is elegant in its simplicity. The patients come in. They get a provocation test, either a FricT est—it's a scratch test to induce their urticaria in symptomatic dermographism—or they get a temp test to induce the cold urticaria. We'll expose them to a single dose of briquilimab, and then evaluate them at 12 weeks. I think this was the study that initially brought a lot of excitement to the mast cell community and the urticaria community when Celldex presented their first data here... and demonstrated a nice complete response rate in this patient population. So, we're expecting the same thing by our ability to deplete mast cells. Okay, that makes sense. Given that it's a pretty small study, 15 patients, how quickly are you kind of expecting to enroll that, and when should we be expecting initial data from that study? You're right, it's a modest sample size. It's an N of 15. The first patient came on that study about a week and a half ago. We would expect that those data would be available in the second half of this year, and probably, you know, close to on the heels of the data from the initial report from the CSU study. Okay, great. Maybe characterize how large the CSU and CIndU markets are, and how you kind of think about the opportunity for briquilimab? Sure. Well, we think that... and if you were at Quad AI this year, CSU seemed to be the indication of interest, and certainly mast cells at this year's quad AI. And there's a lot of interest here and a lot of drug development going on, and I think the consistent theme is that it's an under-diagnosed and under-reported disease at this point. While the market, you know, in the more than a million patients, is certainly a large market, and as it sits currently, I think most people believe that a good analog here is probably the psoriatic market, if you move back a few years when only methotrexate was available, similar to the CIndU market now, where it's antihistamines and Xolair. Fast-forward in that psoriasis market now, where there are eight-10 different drugs that are approved, and they all do at least $2 billion. And so, I think we would expect something similar happening here in the CSU and CIndU market. So, a very large market opportunity, an opportunity we think that with a safe drug and potentially a drug that could only be administered on, maybe on a quarterly basis, that really could bring the derm community back into play here, where currently most of these patients are referred to allergists or immunologists and away from the derms, and we think that it could bring the derms back into play here. We really like our competitive position. We know that there are a number of other modalities that are in development. But at a risk of being overly reductive, the only other mechanism that is depleting mast cells is barzolvolimab. All of the other mechanisms under evaluation are inhibitory. And whether it's back to your question about anaphylaxis or just the underlying disease, with all of those approaches, you need to maintain constant signal inhibition in order to control the disease. And it is a rare opportunity where you know the perpetrating T-cell, and you have an opportunity to deplete it. And I think you know a good analog here is a drug that I worked on many years ago, rituximab, started out as a lymphoma drug, depleting B cells, and we now know you know where all that's gone. When you can actually deplete the perpetrating cell, it's at the apex of the treatment paradigm. That was a great summary. Maybe... and are there any other mast cell-driven diseases that you think briquilimab could be effective for, and do you have any plans in place to evaluate any of those? Absolutely. So, we will start another clinical trial in a mast cell-driven or mast cell-mediated disease this year. It's our commitment to build out a full portfolio. We think that briquilimab is the definition of a portfolio in a product. There are probably better than 20 or 30 different mast cell mediated or driven diseases that we're currently evaluating. Again, we think we have a strategic advantage in the Jasper Mouse that enables us to look in an animal model whether what is the role of the mast cell and how using briquilimab might be important in those diseases. In an oversimplification, we think that any disease that is mast cell-mediated or mast cell-driven presents an opportunity. That may mean different dosing strategies or different dose levels or intervals for those patients, but we look forward to that opportunity. Perfect. Sounds like a very busy and exciting year for you. Looking forward to seeing the updates. Well, thank you very much, Ronald, and thanks everyone for tuning in. We'll conclude the call here. Thank you, Emily.