Good afternoon, everybody and thank you once again for joining us at our first Chronic Urticaria Summit. I'm Yaron Werber from the TD Cowen Biotech team, and with me, it's a great pleasure to introduce Ron Martell, CEO of Jasper Therapeutics. Ron, thanks for joining us. We appreciate it. Yaron, greatly appreciated on behalf of all of my colleagues here at Jasper. We'd like to thank you and TD Cowen for all of your support. Fantastic. So there's a lot to talk about in the field. This is really... Attendance has been great at this urticaria symposium. I think it's a testament to how much is going on, and a lot going on, literally. I mean, next week, we're gonna get the next data cut at 52 weeks from Barzol, and then your data, obviously, from Beacon coming probably later on in Q4. So, you know, as you think of briquilamb, can you give us a little bit of a sense maybe, as you think about the overall profile, kind of how do you, you know, how do you think it's gonna shake out within the field? Yeah, I think I'm excited to hear that you're saying your conference is really well attended. I guess it's not surprising. Someone said to me earlier this year that mast cells are having their moment. I think that's absolutely correct. If you attend any of these conferences from AAAAI to EADV, the college meeting coming up in a couple of weeks, the vast majority of the posters and presentations are centered around mast cells. To specifically answer your question about briquilimab, briquilamb, and its application in this setting, we know that c-Kit is the primary survival pathway for mast cells, and the most efficient way to shut down that signal is with the monoclonal antibody. The specificity that an antibody provides is unsurpassed by any other modality, and the ability to shut down all downstream signaling, thereby resulting in apoptosis and mast cell depletion. We certainly believe that, you know, when you think across all of the drugs that are in development, there's only two drugs that right now in development that can show that they actually deplete mast cells. So I think we couldn't find ourselves in a better position with a better molecule. You know, your drug specifically blocks the interaction of the ligand, the Stem Cell Factor to the receptor. Other drugs provided they block the dimerization of the receptor. Can you talk about why does that matter, if at all? Certainly. Well, you know, if you just empirically think about using an antibody, and you were designing it, whether it's for c-Kit, or you're designing an antibody in oncology or any other application, if you have the ability, you would design it to block at the epitope of the natural ligand. The lock and key metaphor has been used many times, and if you can block where that key, the natural ligand, binds to the epitope, it's proven that you can bind with the highest affinity and avidity. So, that is the primary modality or methodology you would use. Blocking further downstream at the dimerization point, the natural ligand could still bind in the presence of an anti-dimerization antibody, and therefore, there's a possibility of some signal leakage, and there may be a difference in potency. Okay, and is there any way to test that in cell cultures or any animal models? There is the challenge with looking at comparing data. So companies present their IC50s or IC90s. The difference is that you really, if you wanna really compare them, you have to do them in the same study, under the same conditions, because it's really difficult to compare across the different types of cell lines or the conditions if the temperature isn't the same or otherwise. And so, it's always difficult to just compare cross-study comparison. We attempted to do that with a Barzo lookalike, if you will. So we made a version of that, we call it JSP084. We presented some data earlier this summer on that, where under those conditions and with the caveat that it clearly is not Barzo, it looked like briquilimab was more potent, but it comes with a pretty broad range of caveats. Got it. Okay. Can we talk a little bit about... You know, one of the questions we get a lot is the half-life of nine days and how that translates into durable PD activity. Specifically, you're gonna be dosing even Q8 weeks and Q12 weeks. You know, Barzo has a longer half-life, and they're even dosing Q8, Q4, and Q8. So can you talk about some of your PD data and what gives you, you know, conviction on the dosing frequency? Sure. So, we took an approach here towards treating this disease from an optimum biologic dosing standpoint. So we're following the biology of the mast cells, starting with the biology of the mast cell back to what we previously discussed about shutting down c-kit, initiating apoptosis, depleting mast cells. And then, it's also understood that the return kinetics for mast cells are such that mast cells take a long time for the body to produce. They're very energy expensive, and it takes a long time to really repopulate. So, our strategy is more of a Cmax story than an AUC story. So we believe that there's a threshold of concentration required to initiate that apoptosis, and then aligning that with the timing of the return of the mast cells that we think leaning into the shorter half-life, if we're able to deplete the mast cells and give the patients as long of a drug-free interval before the symptoms come back, correlating to the mast cell return, that we might end up with a better safety profile. So our strategy is around the biology of the mast cell, as opposed to maintaining constant inhibition levels of the drug on board for these patients. Oops. When you're gonna look at the data, you know, because the study is small, what kind of delta do you want to see, or what kind of data do you want to see to get comfortable that Q-eight weeks is good enough or even Q-12, or perhaps even contemplate going back to Q-four? I guess I'm asking because the response rate looked the same on Barzolvolimab, but there was a slightly higher CR. I think it was, like, a 14%- Right ... delta in CR, with, you know, deeper CRs with a Q-four-week dosing. Yeah. So, from an overall standpoint, we view this study as very much a success. If we have efficacy in at least one of the cohorts where the data look comparable to Barzo, that means we have a drug. We are the definition of a fast follower. We're only twelve-ish months behind them, and we're racing towards the path to a registrational program. To your point about the sample size, it is a modest sample size, and while the study is placebo-controlled, it's not placebo-controlled from a statistical standpoint. It's placebo-controlled from a study conduct standpoint, given that this is a patient-reported outcome. So we felt it really important that everyone be blinded in this study as to not affect the outcome. I think that, you know, the primary thing we're looking at is certainly disease control. Physicians tell us that that's the most important outcome. Complete response is, of course, really nice, but the fact is, they're looking for a drug that they can ensure that all of their patients, or most of their patients, are going to benefit from. And so I think, you know, at the top, we're looking for disease control, and then we'll be looking to see also, yes, if we do have anybody that has a complete response. I think the challenge at the moment is trying to understand, and this is what we'll hopefully be able to do in this study, is how does mast cell depletion correlate with level of efficacy? Unfortunately, we haven't seen that data from Barzol. We've seen their top-line efficacy data, but we don't know the depth of depletion that's necessary. And is the depth of depletion correlated between disease control or complete response, or is this just one of those patient-reported outcomes that you know, different patients perceive their disease differently? How do you-- how are you thinking about tryptase levels? 'Cause they, they do recur earlier, and they, they are presumably coming from the mast cells. Yeah. So we absolutely agree that tryptase is a good leading-edge biomarker for mast cell depletion. It absolutely correlates to mast cell depletion. Where there's a biologic disconnect with serum tryptase is on the return of the mast cells to the skin. So first, it's important to understand that serum tryptase is a measure of total body mast cells, and you not only have mast cells in your skin, but you have them in your lung, your gut. I mean, sorry, the appendix is loaded with mast cells. And the hypothesis is that evolutionary biology has taught the body that it needs to repopulate those tissues sooner than the skin. So the serum tryptase could be picking up the repopulation of those tissues. Because it's not specific to the skin, it's picking up the return of the population to those. The other thing about serum tryptase is that it is a measure of both alpha and beta or inactive and active tryptase. It's well known in the field that progenitor mast cells, they're immature mast cells that are not able to degranulate yet. They're either circulating, moving towards their destined tissue, or once they arrive in that tissue, it takes them a while to mature to where they could degranulate. That entire time, they're making tryptase. So is that early tryptase that you're seeing come back, is that more inactive tryptase from the progenitors?... And that's why it seems to be a bit of a disconnect between the return of the tryptase and the durability of symptom control, even when the drug is off. Okay, got it. And by the way, for the audience, if you have any questions, feel free to, you know, put them into the Wall Street Webcasting little box. We can see them here, or feel free to email me directly, and I'll be happy to take them on your behalf. Okay, so when we see the beacon data, I mean, there's going to be part one, which is the 10 and 40 mgs, which you need to do just to check the box for FDA and dose response and super non-therapeutic, you know, below therapeutic levels. Then there's really the 80 to the 180, which I believe we're going to get that data in Q4, and then the 240 single dose, that's probably going to come early next year, potentially at Quad AI, February 28th to March 3rd. Am I thinking about this correctly on just timing for data? A slight clarification on that. So you're absolutely correct. The 10 and the 40 are of interest to us as a drug developer and interest to the agency. And part two is where we arrive at what we think, begin at the 80 milligram level to cross that threshold of concentration and where we expect to see some activity, but we certainly expect to see better activity at the 120 and the 180 level. Now, clarification here on the timing of the data is, we are absolutely confident that in Q4, we can provide data from all the original cohorts in the study through the 240. So, what we need to clarify is, so we recently added a new cohort, 180 milligrams Q8 week, and those data might be available in Q4. We're keeping an eye on enrollment in that group, and should we enroll that study in time, then we'll have that data in Q4 as well. So, we will have the two all the way through the 240, and might have the new cohort, the 180 Q8. And what we're continuing to evaluate is if the time difference between having that 180 Q8 and all the data all the way through the 240 is only a matter of a couple of weeks, then that could push out the timing to early January, and we may make that decision to do that. But we will have all of the data through 240 by the end of the year. Okay, got it. But either way, it sounds like we'll, even when we're talking about Q4, we're probably talking about December. Correct. And then there's some chance that it could fall into early January. That's correct. And we will provide some guidance in the coming weeks on that as well. Yeah. So, it will be very clear when we will have the data and when we'll be reporting it out. And then you're targeting full data at Quad AI? That's correct. That's correct. Got it. So the primary endpoint, you know, so to speak, I mean, this is obviously a small study, so safety is very paramount. But then the initial efficacy on UAS7 is at week 12. And again, it depends on the way it works. Patients are going to get dosed day zero and week 8, and then there's going to be an assessment, obviously, at week 12. So in some cases where patients are getting Q12-week dosing, they'll have day zero, and then week 12, and at week 12, they're already doing the first efficacy assessment too. We know with c-Kit inhibitions, there's a fast onset of action. On Wednesday, we'll see the Barzo 52-week data, and I think that's going to inform us of where does the efficacy actually plateau, because it looked like it was trending downwards at the 12-week endpoint from their phase II. So I guess my question is, it's also very important for... I guess my question to you, we're all going to go immediately look at week 12 for the, let's say, another compound in the class versus yours. Yeah. Another compound in the class, they would have had dosing either Q4, or I guess they would have had Q8 weeks. But I guess the question is, is it fair to compare then your week 12 in patients that got Q12-week dosing? Because at that point, I mean, we are comparing one dose to, I guess, for them, potentially two doses on the Q8 and three doses on the Q4. That's correct. So, is it fair? Life isn't fair, but we know people will do that. We know everyone will do that, and we specifically chose the 12-week as an endpoint because that's what Celldex did. The endpoint doesn't have to be 12 weeks. If you look at what Remi did or what Dupi has done, it doesn't have to be 12 weeks. But so you will be able to compare that, and for this initial data report, we will have on some of the patients follow-up, further follow-up, so after their second dose at 12 weeks, and then certainly at the college. So you'll be able to see at by... or I'm sorry, at Quad AI, you'll be able to see a potential impact from that second dose at twelve weeks as well. And that'll be a conversation, you know, that we'll have with the agency for briquilimab, what's the appropriate time interval for assessment based on our dose? And so based on this data, and we're talking about cohorts that are anywhere between six patients, you know, the 120s or six patients, the 80s or eight, and the 180s or eight. You know, with all that data, you know, as you think about identifying a dose and moving forward, whether it's gonna be right into a phase 3 or into a phase 2/3, how do you... Kind of, what do you want to see to be able to go right into phase three, as opposed to going into another kind of a lead-in phase two, maybe when you're still comparing one or two doses or so, or two doses, and into phase three? I think the data will drive that. If we have a clear winner, then it makes that decision a bit easier, to you know, be able to absolutely pick a dose and move forward. I think to your point, if we see two different doses that have similar efficacy, do we run those in a phase 2b, 3 adaptive design, such that you know, we can apply all those patients to the registrational trial and rapidly move forward? Those will be conversations we'll have with the agency soon. Ultimately, I mean, we're working on those designs now, and it'll be driven by the data. I think the other interesting thing here is, you know, the last cohort in the study, in part three, at the 240 level, we put that in this study early on, thinking about the concept of a loading dose. And so, you know what? It'll be interesting to see, as a single dose, at a higher level, does that impact the depth of depletion? And does the depth of depletion further affect the return kinetics? And so, that will be quite informative as well to help us ultimately design our registrational program. In this study, how long are patients going to be dosed for? Is it, I know part one is until that's the 10 and the 40 until 20. Part two, which is the 80 to 180, is, you know, up to 24 weeks. At that point, do they get to, does the placebo get to cross over to active with a longer term extension? Do people on active drug stay on drug with a longer term extension, or do you stop dosing at that point, and you look at return kinetics again and kind of...? We will continue to dose, and we'll provide some clarity soon on a rollover crossover, if you will, for all of these patients. So that's a part of the protocol? That's correct. Okay. Got it. So the best data to look at real durability will be the 240 single dose. Well, that will give you the durability, yes. That's right ... as a single dose. Yeah. That, that's correct. Yeah. and, you know- But- ... it's, it'll be the highest Cmax that we'll achieve in this study, and so it will give you the best understanding of both depletion and the return kinetics. That's correct. Yeah. But since you're continuing in the OLE at Q8 and Q12, you'll have that PD markers anyway. Correct. And then, you know, as you think about the data, what would drive you to say, "Hey, you know, maybe we should do a Q4 week dosing too next? Yeah, I think what could potentially tell us that is if at the different dose levels we're having the return of the mast cells or the return of the clinical symptoms earlier, which would suggest that we need to have more drug on board earlier. But then to your point, you also have, at the same time, the other side of that coin is you have the 240 mg loading dose as a potential loading dose. So you'll just have to kind of make a judgment call based on the data as to what to do next. That's correct. Okay. Got it. You know, one of the questions that we ask is about exposure, just given the nine-day half-life. Do you see any accumulation? Kind of, what do you see from an exposure perspective? Given our Q8-week and Q12-week dosing schedule with a nine-day half-life, the drug is completely cleared by the time they receive their next dose. So. And if you're thinking, you know, sort of in a three, three and a half half-lives, then, you know, the drug is cleared out thirty-ish days, and you're below that threshold. And by the time the eight weeks rolls around, the drug is completely cleared, so there is no accumulation in this dosing schedule. And that's why it could translate into a better safety profile by not having c-kit. Mast cells are the largest sink of c-kit in the body. And so if you've completely depleted them or substantially depleted them, and you still have therapeutic levels of antibody on board, that antibody will target those other c-kit-presenting cells that lead to those on-target AEs. And just remind us, you know, the PD marker is also mast cell repopulation. You are doing skin biopsies, I believe, in BEACON. Would that data be ready for Quad AI? Because that data obviously is more complicated to interpret than just analyze and read out. That's right. That's a good point. So those data won't be available at the top-line data analysis that we're currently guiding towards. But we would expect to have those for Quad AI. That's correct. So when we report the initial data from this study, we'll have the UAS7 and UCT at 12 weeks. We'll have serum tryptase and safety data on all of these patients. Right. Okay, and then the CIndU study, the SPOTLIGHT study is also ongoing. Can you just remind us the timing for that? And, of course, that's a very different trial design. That's cohort one only with a 40 mg dose. Very small sort of POC, and then you go into... Actually, I'm sorry, you have a cohort two at 120 as well. Correct. So, there's 15 total patients in that study. Three of the patients are receiving the 40, again, subtherapeutic, minimally effective dosing, and then 12 patients at the 120 dose. So this study is very much akin to the first Celldex CIndU study, where patients will receive a single dose of briquilimab, and we'll follow them and have routine provocation tests over the 12-week period of time, just like they conducted their first study. The patient population we're enrolling is two types of inducible urticarias, symptomatic dermographism, and cold urticaria. So again, very much like what Celldex did. The patients come in on day zero, receive their provocation test associated with their urticaria, then they'll receive briquilimab, and then come back every couple of weeks for a repeat provocation test. To go back to the BEACON study, your frequency of ADAs have been low. I think there's only been one case of anaphylaxis in Amgen's original healthy volunteer cohort. Can you talk about what you've said so far and, you know, anything that you can add on the BEACON study as well from a safety perspective so far? Sure. So yes, to date, what we've observed with briquilimab, with the SubQ formulation, and so that's important, is that, we've seen about 14% ADAs, and those ADAs have not affected the PK or PD of the drug. It's known that SubQ drugs tend to have a higher ADA rate than IV drugs. Subq gets into all five compartments, and so you generally have a slightly higher rate of ADAs with a SubQ drug. Specifically related to that one subject in the healthy volunteer study from the Amgen study, yes, there was a reported grade 3 incident in that study. Having said that, on further review of that subject, and we reviewed this in detail with the FDA. So that subject presented 36 hours after their SubQ injection of briquilimab. So 36 hours makes it suspect, but at the same time, you know, it's... you can't rule that out. There are very idiosyncratic cases that happen. Having said that, there was only one organ system involved, the skin. There were no change in vital signs at all, no change in respiratory, blood pressure, drop in temp, no rescue meds like epinephrine. The subject was observed for two hours and then sent home. It certainly appears as if that was an over-grading, but it's in the final CSR. Having said that, that's why it's really important, prior to the implementation and the filing of the IND, we worked very closely with the FDA to put in an adjudication committee. So there's very clear rules for how do you score an infusion reaction, an anaphylaxis, you know, whatever you might wanna call these, because we didn't wanna be adjudicating these after the fact with the FDA. So it's really important that we put that in place. What I can say at this point is that we've had no incidents such as that in the BEACON or SPOTLIGHT study. All right. Well, terrific. I think, Ron, we are exactly at time. So thanks so much for joining us. We appreciate it, and we'll continue to be in close touch. Sounds great, Yaron. Really appreciate it. Thank you. Yep. Thank you.